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Pharmaceutics
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Kinase Inhibitor for Cancer Therapy
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Kinase Inhibitor for Cancer Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 57071

Special Issue Editor

Dr. Francesca Musumeci

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Interests: pyrazolo[3,4-d]pyrimidines; kinase inhibitors; anticancer agents; small molecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is one of the leading causes of death worldwide, and still, considerable effort is needed to make this pathology curable. Despite the limits of available approaches, kinase inhibitors have marked a turning point in the treatment of different types of tumors. This class of compounds has been the first oral targeted therapy approved for neoplasia, and about 30 compounds have entered the market in the last five years. Kinase inhibitors include small molecules and monoclonal antibodies and are endowed with fewer side effects than classical antitumor agents. The potential for application of this class of drugs is still huge, and this Special Issue focuses on the discovery and development of kinase inhibitors in terms of in silico studies, synthesis and identification of new compounds, drug delivery, formulation studies, and biological and pharmacokinetic evaluation.

In this Special Issue, original research articles and reviews are welcome.

I look forward to receiving your contributions.

Dr. Francesca Musumeci
Guest Editor

Manuscript Submission Information

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Keywords

  • kinase inhibitor
  • cancer
  • targeted therapy
  • small molecule
  • monoclonal antibody
  • drug delivery
  • formulation studies

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Published Papers (23 papers)

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Research

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26 pages, 13094 KiB  
Article
Synthesis and Anticancer Activity of Novel Dual Inhibitors of Human Protein Kinases CK2 and PIM-1
by Patrycja Wińska, Monika Wielechowska, Mirosława Koronkiewicz and Paweł Borowiecki
Pharmaceutics 2023, 15(7), 1991; https://doi.org/10.3390/pharmaceutics15071991 - 20 Jul 2023
Cited by 2 | Viewed by 1484
Abstract
CK2 and PIM-1 are serine/threonine kinases involved in the regulation of many essential processes, such as proliferation, differentiation, and apoptosis. Inhibition of CK2 and PIM-1 kinase activity has been shown to significantly reduce the viability of cancer cells by inducing apoptosis. A series [...] Read more.
CK2 and PIM-1 are serine/threonine kinases involved in the regulation of many essential processes, such as proliferation, differentiation, and apoptosis. Inhibition of CK2 and PIM-1 kinase activity has been shown to significantly reduce the viability of cancer cells by inducing apoptosis. A series of novel amino alcohol derivatives of parental DMAT were designed and synthesized as potent dual CK2/PIM-1 inhibitors. Concomitantly with the inhibition studies toward recombinant CK2 and PIM-1, the influence of the obtained compounds on the viability of three human carcinoma cell lines, i.e., acute lymphoblastic leukemia (CCRF-CEM), human chronic myelogenous leukemia (K-562), and breast cancer (MCF-7), as well as non-cancerous cells (Vero), was evaluated using an MTT assay. Induction of apoptosis and cell cycle progression after treatment with the most active compound and a lead compound were studied by flow-cytometry-based assay. Additionally, autophagy induction in K-562 cells and intracellular inhibition of CK2 and PIM-1 in all the tested cell lines were evaluated by qualitative/quantitative fluorescence-based assay and Western blot method, respectively. Among the newly developed inhibitors, 1,1,1-trifluoro-3-[(4,5,6,7-tetrabromo-1H-benzimidazol-2-yl)amino]propan-2-ol demonstrates the highest selectivity and the most prominent proapoptotic properties towards the studied cancer cells, especially towards acute lymphoblastic leukemia, in addition to inducing autophagy in K-562 cells. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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19 pages, 2376 KiB  
Article
An Aptamer against MNK1 for Non-Small Cell Lung Cancer Treatment
by Rebeca Carrión-Marchante, Celia Pinto-Díez, José Ignacio Klett-Mingo, Esther Palacios, Miriam Barragán-Usero, M. Isabel Pérez-Morgado, Manuel Pascual-Mellado, Sonia Alcalá, Laura Ruiz-Cañas, Bruno Sainz, Jr., Víctor M. González and M. Elena Martín
Pharmaceutics 2023, 15(4), 1273; https://doi.org/10.3390/pharmaceutics15041273 - 18 Apr 2023
Viewed by 1273
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall [...] Read more.
Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall survival in non-small cell lung cancer (NSCLC) patients. The previously identified and optimized aptamer from our laboratory against MNK1, apMNKQ2, showed promising results as an antitumor drug in breast cancer in vitro and in vivo. Thus, the present study shows the antitumor potential of apMNKQ2 in another type of cancer where MNK1 plays a significant role, such as NSCLC. The effect of apMNKQ2 in lung cancer was studied with viability, toxicity, clonogenic, migration, invasion, and in vivo efficacy assays. Our results show that apMNKQ2 arrests the cell cycle and reduces viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in NSCLC cells. In addition, apMNKQ2 reduces tumor growth in an A549-cell line NSCLC xenograft model. In summary, targeting MNK1 with a specific aptamer may provide an innovative strategy for lung cancer treatment. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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16 pages, 2716 KiB  
Article
A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells
by Amineh Ghaderi, Mohammad-Ali Okhovat, Jemina Lehto, Luigi De Petris, Ehsan Manouchehri Doulabi, Parviz Kokhaei, Wen Zhong, Georgios Z. Rassidakis, Elias Drakos, Ali Moshfegh, Johan Schultz, Thomas Olin, Anders Österborg, Håkan Mellstedt and Mohammad Hojjat-Farsangi
Pharmaceutics 2023, 15(4), 1148; https://doi.org/10.3390/pharmaceutics15041148 - 05 Apr 2023
Cited by 2 | Viewed by 3185
Abstract
The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N [...] Read more.
The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of a small molecule ROR1 inhibitor (KAN0441571C) in NSCLC cell lines. ROR1 expression in tumor cells was more frequent in non-squamous (87%) than in squamous (57%) carcinomas patients, while 21% of neuroendocrine tumors expressed ROR1 (p = 0.0001). A significantly higher proportion of p53 negative patients in the ROR1+ group than in the p53 positive non-squamous NSCLC patients (p = 0.03) was noted. KAN0441571C dephosphorylated ROR1 and induced apoptosis (Annexin V/PI) in a time- and dose-dependent manner in five ROR1+ NSCLC cell lines and was superior compared to erlotinib (EGFR inhibitor). Apoptosis was confirmed by the downregulation of MCL-1 and BCL-2, as well as PARP and caspase 3 cleavage. The non-canonical Wnt pathway was involved. The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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15 pages, 848 KiB  
Article
Biological Evaluation and In Vitro Characterization of ADME Profile of In-House Pyrazolo[3,4-d]pyrimidines as Dual Tyrosine Kinase Inhibitors Active against Glioblastoma Multiforme
by Federica Poggialini, Chiara Vagaggini, Annalaura Brai, Claudia Pasqualini, Emmanuele Crespan, Giovanni Maga, Cecilia Perini, Noemi Cabella, Lorenzo Botta, Francesca Musumeci, Maria Frosini, Silvia Schenone and Elena Dreassi
Pharmaceutics 2023, 15(2), 453; https://doi.org/10.3390/pharmaceutics15020453 - 30 Jan 2023
Cited by 5 | Viewed by 1526
Abstract
The therapeutic use of tyrosine kinase inhibitors (TKIs) represents one of the successful strategies for the treatment of glioblastoma (GBM). Pyrazolo[3,4-d]pyrimidines have already been reported as promising small molecules active as c-Src/Abl dual inhibitors. Herein, we present a series of pyrazolo[3,4- [...] Read more.
The therapeutic use of tyrosine kinase inhibitors (TKIs) represents one of the successful strategies for the treatment of glioblastoma (GBM). Pyrazolo[3,4-d]pyrimidines have already been reported as promising small molecules active as c-Src/Abl dual inhibitors. Herein, we present a series of pyrazolo[3,4-d]pyrimidine derivatives, selected from our in-house library, to identify a promising candidate active against GBM. The inhibitory activity against c-Src and Abl was investigated, and the antiproliferative profile against four GBM cell lines was studied. For the most active compounds endowed with antiproliferative efficacy in the low-micromolar range, the effects toward nontumoral, healthy cell lines (fibroblasts FIBRO 2-93 and keratinocytes HaCaT) was investigated. Lastly, the in silico and in vitro ADME properties of all compounds were also assessed. Among the tested compounds, the promising inhibitory activity against c-Src and Abl (Ki 3.14 µM and 0.44 µM, respectively), the irreversible, apoptotic-mediated death toward U-87, LN18, LN229, and DBTRG GBM cell lines (IC50 6.8 µM, 10.8 µM, 6.9 µM, and 8.5 µM, respectively), the significant reduction in GBM cell migration, the safe profile toward FIBRO 2-93 and HaCaT healthy cell lines (CC50 91.7 µM and 126.5 µM, respectively), the high metabolic stability, and the excellent passive permeability across gastrointestinal and blood–brain barriers led us to select compound 5 for further in vivo assays. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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17 pages, 3522 KiB  
Article
Influence of Lenvatinib on the Functional Reprogramming of Peripheral Myeloid Cells in the Context of Non-Medullary Thyroid Carcinoma
by Chunying Peng, Katrin Rabold, Mihai G. Netea, Martin Jaeger and Romana T. Netea-Maier
Pharmaceutics 2023, 15(2), 412; https://doi.org/10.3390/pharmaceutics15020412 - 26 Jan 2023
Cited by 2 | Viewed by 1549
Abstract
Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and [...] Read more.
Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data has revealed that most of the TKIs have additional ‘off-target’ immunological effects, which might contribute to a protective antitumor immune response; however, human cellular data are lacking regarding Lenvatinib-mediated immunomodulation in DTC. Here, we investigated in ex vivo models the impact of Lenvatinib on the function of immune cells in healthy volunteers. We found that monocytes and macrophages were particularly susceptible to Lenvatinib, while neutrophiles and lymphocytes were less affected. In tumor-immune cell co-culture experiments, Lenvatinib exerted a broad inhibitory effect on the proinflammatory response in TC-induced macrophages. Interestingly, Lenvatinib-treated cells had decreased cellular M2 membrane markers, whereas they secreted a significantly higher level of the anti-inflammatory cytokine IL-10 upon LPS stimulation. In addition, prolonged exposure to Lenvatinib impaired macrophages survival and phenotypical differentiation, which was accompanied by remarkable morphological changes and suppressed cellular metabolic activity. These effects were mediated by myeloid cell-intrinsic mechanisms which are independent of Lenvatinib’s on-target activity. Finally, using specific inhibitors, we argue that dual effects on p38 MAPK and Syk pathways are likely the underlying mechanism of the off-target immunological effects we observed in this study. Collectively, our data show the immunomodulatory properties of Lenvatinib on human monocytes. These insights could be harnessed for the future design of novel treatment strategies involving a combination of Lenvatinib with other immunotherapeutic agents. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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13 pages, 2451 KiB  
Article
Comparative Analysis of Dasatinib Effect between 2D and 3D Tumor Cell Cultures
by Samantha Sabetta, Davide Vecchiotti, Letizia Clementi, Mauro Di Vito Nolfi, Francesca Zazzeroni and Adriano Angelucci
Pharmaceutics 2023, 15(2), 372; https://doi.org/10.3390/pharmaceutics15020372 - 21 Jan 2023
Cited by 7 | Viewed by 1809
Abstract
Three-dimensional cell culture methods are able to confer new predictive relevance to in vitro tumor models. In particular, the 3D multicellular tumor spheroids model is considered to better resemble tumor complexity associated with drug resistance compared to the 2D monolayer model. Recent advances [...] Read more.
Three-dimensional cell culture methods are able to confer new predictive relevance to in vitro tumor models. In particular, the 3D multicellular tumor spheroids model is considered to better resemble tumor complexity associated with drug resistance compared to the 2D monolayer model. Recent advances in 3D printing techniques and suitable biomaterials have offered new promises in developing 3D tissue cultures at increased reproducibility and with high-throughput characteristics. In our study, we compared the sensitivity to dasatinib treatment in two different cancer cell lines, prostate cancer cells DU145 and glioblastoma cells U87, cultured in the 3D spheroids model and in the 3D bioprinting model. DU145 and U87 cells were able to proliferate in 3D alginate/gelatin bioprinted structures for two weeks, forming spheroid aggregates. The treatment with dasatinib demonstrated that bioprinted cells were considerably more resistant to drug toxicity than corresponding cells cultured in monolayer, in a way that was comparable to behavior observed in the 3D spheroids model. Recovery and analysis of cells from 3D bioprinted structures led us to hypothesize that dasatinib resistance was dependent on a scarce penetrance of the drug, a phenomenon commonly reported also in spheroids. In conclusion, the 3D bioprinted model utilizing alginate/gelatin hydrogel was demonstrated to be a suitable model in drug screening when spheroid growth is required, offering advantages in feasibility, reproducibility, and scalability compared to the classical 3D spheroids model. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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21 pages, 3876 KiB  
Article
Micellar Curcumin Substantially Increases the Antineoplastic Activity of the Alkylphosphocholine Erufosine against TWIST1 Positive Cutaneous T Cell Lymphoma Cell Lines
by Antonios G. X. Trochopoulos, Yana Ilieva, Alexander D. Kroumov, Lyudmila L. Dimitrova, Ivanka Pencheva-El Tibi, Stanislav Philipov, Martin R. Berger, Hristo M. Najdenski, Krassimira Yoncheva, Spiro M. Konstantinov and Maya M. Zaharieva
Pharmaceutics 2022, 14(12), 2688; https://doi.org/10.3390/pharmaceutics14122688 - 01 Dec 2022
Cited by 1 | Viewed by 1485
Abstract
Cutaneous T-cell lymphoma (CTCL) is a rare form of cancer with local as well as systemic manifestations. Concomitant bacterial infections increase morbidity and mortality rates due to impaired skin barrier and immune deficiency. In the current study, we demonstrated that the in vitro [...] Read more.
Cutaneous T-cell lymphoma (CTCL) is a rare form of cancer with local as well as systemic manifestations. Concomitant bacterial infections increase morbidity and mortality rates due to impaired skin barrier and immune deficiency. In the current study, we demonstrated that the in vitro anti-lymphoma potential of erufosine is diminished by TWIST1 expression and micellar curcumin substantially increases its antineoplastic activity. Pharmacokinetic analysis showed that the micellar curcumin (MCRM) used in our study was characterized by low zeta potential, slow release of curcumin, and fast cell membrane penetration. The combination ratio 1:4 [erufosine:MCRM] achieved strong synergism by inhibiting cell proliferation and clonogenicity. The combined antiproliferative effects were calculated using the symbolic mathematical software MAPLE 15. The synergistic combination strongly decreased the expression of TWIST1 and protein kinase B/Akt as proven by western blotting. Significant reductions in NF-κB activation, induction of apoptosis, and altered glutathione levels were demonstrated by corresponding assays. In addition, the synergistic combination enhanced the anti-staphylococcal activity and prevented biofilm formation, as shown by crystal violet staining. Taken together, the above results show that the development of nanotechnological treatment modalities for CTCL, based on rational drug combinations exhibiting parallel antineoplastic and antibacterial effects, may prove efficacious. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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16 pages, 1441 KiB  
Article
From Serendipity to Rational Identification of the 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one Core as a New Chemotype of AKT1 Inhibitors for Acute Myeloid Leukemia
by Andrea Astolfi, Francesca Milano, Deborah Palazzotti, Jose Brea, Maria Chiara Pismataro, Mariangela Morlando, Oriana Tabarrini, Maria Isabel Loza, Serena Massari, Maria Paola Martelli and Maria Letizia Barreca
Pharmaceutics 2022, 14(11), 2295; https://doi.org/10.3390/pharmaceutics14112295 - 26 Oct 2022
Cited by 3 | Viewed by 2677
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug [...] Read more.
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug resistance. Against this backdrop, very recently we have started a multidisciplinary research project focused on AKT1 as a pharmacological target to identify novel anti-AML agents. Indeed, the serendipitous finding of the in-house compound T187 as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which T126 has emerged as the most interesting compound with IC50 = 1.99 ± 0.11 μM, ligand efficiency of 0.35, and a clear effect at low micromolar concentrations on growth inhibition and induction of apoptosis in AML cells. The collected results together with preliminary SAR data strongly indicate that the 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one derivative T126 is worthy of future biological experiments and medicinal chemistry efforts aimed at developing a novel chemical class of AKT1 inhibitors as anti-AML agents. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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13 pages, 2426 KiB  
Article
A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells
by Amineh Ghaderi, Wen Zhong, Mohammad Ali Okhovat, Johanna Aschan, Ann Svensson, Birgitta Sander, Johan Schultz, Thomas Olin, Anders Österborg, Mohammad Hojjat-Farsangi and Håkan Mellstedt
Pharmaceutics 2022, 14(10), 2238; https://doi.org/10.3390/pharmaceutics14102238 - 20 Oct 2022
Cited by 4 | Viewed by 2177
Abstract
The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small [...] Read more.
The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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20 pages, 32534 KiB  
Article
Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors
by Michael E. Stokes, Matthew D. Surman, Veronica Calvo, David Surguladze, An-Hu Li, Jennifer Gasparek, Matthew Betzenhauser, Guangyu Zhu, Hongwen Du, Alan C. Rigby and Mark J. Mulvihill
Pharmaceutics 2022, 14(10), 2233; https://doi.org/10.3390/pharmaceutics14102233 - 19 Oct 2022
Cited by 3 | Viewed by 1877
Abstract
The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as [...] Read more.
The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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16 pages, 1825 KiB  
Article
Bruton’s Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux
by Lucie Čermáková, Jakub Hofman, Lenka Laštovičková, Lucie Havlíčková, Ivona Špringrová, Eva Novotná and Vladimír Wsól
Pharmaceutics 2022, 14(10), 1994; https://doi.org/10.3390/pharmaceutics14101994 - 21 Sep 2022
Cited by 5 | Viewed by 2025
Abstract
Zanubrutinib (ZAN) is a Bruton’s tyrosine kinase inhibitor recently approved for the treatment of some non-Hodgkin lymphomas. In clinical trials, ZAN is often combined with standard anthracycline (ANT) chemotherapy. Although ANTs are generally effective, drug resistance is a crucial obstacle that leads to [...] Read more.
Zanubrutinib (ZAN) is a Bruton’s tyrosine kinase inhibitor recently approved for the treatment of some non-Hodgkin lymphomas. In clinical trials, ZAN is often combined with standard anthracycline (ANT) chemotherapy. Although ANTs are generally effective, drug resistance is a crucial obstacle that leads to treatment discontinuation. This study showed that ZAN counteracts ANT resistance by targeting aldo-keto reductase 1C3 (AKR1C3) and ATP-binding cassette (ABC) transporters. AKR1C3 catalyses the transformation of ANTs to less potent hydroxy-metabolites, whereas transporters decrease the ANT-effective concentrations by pumping them out of the cancer cells. In our experiments, ZAN inhibited the AKR1C3-mediated inactivation of daunorubicin (DAUN) at both the recombinant and cellular levels. In the drug combination experiments, ZAN synergistically sensitised AKR1C3-expressing HCT116 and A549 cells to DAUN treatment. Gene induction studies further confirmed that ZAN did not increase the intracellular level of AKR1C3 mRNA; thus, the drug combination effect is not abolished by enzyme induction. Finally, in accumulation assays, ZAN was found to interfere with the DAUN efflux mediated by the ABCB1, ABCG2, and ABCC1 transporters, which might further contribute to the reversal of ANT resistance. In summary, our data provide the rationale for ZAN inclusion in ANT-based therapy and suggest its potential for the treatment of tumours expressing AKR1C3 and/or the above-mentioned ABC transporters. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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18 pages, 5097 KiB  
Article
Vitamin E TPGS-Poloxamer Nanoparticles Entrapping a Novel PI3Kα Inhibitor Potentiate Its Activity against Breast Cancer Cell Lines
by Suhair Sunoqrot, Sundos Aliyeh, Samah Abusulieh and Dima Sabbah
Pharmaceutics 2022, 14(9), 1977; https://doi.org/10.3390/pharmaceutics14091977 - 19 Sep 2022
Cited by 5 | Viewed by 2168
Abstract
N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future [...] Read more.
N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future administration in preclinical and clinical settings. NPs were prepared by nanoprecipitation using two polymers: D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and the poloxamer Pluronic P123 in different ratios. Physicochemical characterization of the NPs revealed them to be around 100 nm in size with high monodispersity, a spherical morphology, and an almost neutral surface charge. The NPs achieved ~60% drug loading efficiency and sustained release of R19 for up to 96 h, with excellent colloidal stability in serum-containing cell culture media. NPs containing TPGS enhanced R19’s potency against MCF-7 and MDA-MB-231 breast cancer cells in vitro, with half-maximal inhibitory concentrations (IC50) ranging between 1.8 and 4.3 µM compared to free R19, which had an IC50 of 14.7–17.0 µM. The NPs also demonstrated low cytotoxicity against human dermal fibroblasts and more significant induction of apoptosis compared to the free drug, which was correlated with their cellular uptake efficiency. Our findings present a biocompatible NP formulation for the delivery of a cancer-targeted PI3Kα inhibitor, R19, which can further enhance its potency for the treatment of breast cancer and potentially other cancer types. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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12 pages, 3918 KiB  
Article
Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors
by Men Thi Hoai Duong and Hee-Chul Ahn
Pharmaceutics 2022, 14(9), 1900; https://doi.org/10.3390/pharmaceutics14091900 - 08 Sep 2022
Cited by 2 | Viewed by 1663
Abstract
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are related to cell proliferation, gene expression, and cell death. JNK isoform 3 (JNK3) is an important therapeutic target in varieties of pathological conditions including cancers and neuronal [...] Read more.
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are related to cell proliferation, gene expression, and cell death. JNK isoform 3 (JNK3) is an important therapeutic target in varieties of pathological conditions including cancers and neuronal death. There is no approved drug targeting JNKs. To discover chemical inhibitors of JNK3, virtual fragment screening, the saturation transfer difference (STD) NMR, in vitro kinase assay, and X-ray crystallography were employed. A total of 27 fragments from the virtually selected 494 compounds were identified as initial hits via STD NMR and some compounds showed the inhibition of the activity of JNK3 in vitro. The structures of JNK3 with a fragment and a potent inhibitor were determined by X-ray crystallography. The fragment and inhibitor shared a common JNK3-binding feature. The result shows that fragment screening by NMR spectroscopy is a very efficient method to screen JNK3 binders and the structure of JNK3-inhibitor complex can be used to design and develop more potent inhibitors. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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11 pages, 2015 KiB  
Article
Kinase Inhibitor Screening Displayed ALK as a Possible Therapeutic Biomarker for Gastric Cancer
by Felipe Pantoja Mesquita, Pedro Filho Noronha Souza, Emerson Lucena da Silva, Luina Benevides Lima, Lais Lacerda Brasil de Oliveira, Caroline Aquino Moreira-Nunes, William J. Zuercher, Rommel Mario Rodríguez Burbano, Maria Elisabete Amaral de Moraes and Raquel Carvalho Montenegro
Pharmaceutics 2022, 14(9), 1841; https://doi.org/10.3390/pharmaceutics14091841 - 01 Sep 2022
Cited by 1 | Viewed by 1367
Abstract
Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a [...] Read more.
Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a novel kinase target in malignant gastric cells as a potential therapeutic strategy. Our results demonstrate that among 147 kinase inhibitors (KI), only three molecules were significantly cytotoxic for the AGP-01 cell line. Hence, these three molecules were further characterized in their cellular mode of action. There was significant cell cycle impairment due to the expression modulation of genes such as TP53, CDKN1A, CDC25A, MYC, and CDK2 with subsequent induction of apoptosis. In fact, the Gene Ontology analysis revealed a significant enrichment of pathways related to cell cycle regulation (GO:1902749 and GO:1903047). Moreover, the three selected KIs significantly reduced cell migration and Vimentin mRNA expression after treatment. Surprisingly, the three KIs share the same target, ALK and INSR, but only the ALK gene was found to have a high expression level in the gastric cancer cell line. Additionally, lower survival rates were observed for patients with high ALK expression in TCGA-STAD analysis. In summary, we hypothesize that ALK gene overexpression can be a promising biomarker for prognosis and therapeutic management of gastric adenocarcinoma. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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12 pages, 3709 KiB  
Article
Anti-Survival Effect of SI306 and Its Derivatives on Human Glioblastoma Cells
by Lorenzo Monteleone, Barbara Marengo, Francesca Musumeci, Giancarlo Grossi, Anna Carbone, Giulia E. Valenti, Cinzia Domenicotti and Silvia Schenone
Pharmaceutics 2022, 14(7), 1399; https://doi.org/10.3390/pharmaceutics14071399 - 01 Jul 2022
Cited by 3 | Viewed by 1270
Abstract
Glioblastoma (GBM) is the most common adult brain tumor and, although many efforts have been made to find valid therapies, the onset of resistance is the main cause of recurrence. Therefore, it is crucial to identify and target the molecular mediators responsible for [...] Read more.
Glioblastoma (GBM) is the most common adult brain tumor and, although many efforts have been made to find valid therapies, the onset of resistance is the main cause of recurrence. Therefore, it is crucial to identify and target the molecular mediators responsible for GBM malignancy. In this context, the use of Src inhibitors such as SI306 (C1) and its prodrug (C2) showed promising results, suggesting that SI306 could be the lead compound useful to derivate new anti-GBM drugs. Therefore, a new prodrug of SI306 (C3) was synthesized and tested on CAS-1 and U87 human GBM cells by comparing its effect to that of C1 and C2. All compounds were more effective on CAS-1 than U87 cells, while C2 was the most active on both cell lines. Moreover, the anti-survival effect was associated with a reduction in the expression of epidermal growth factor receptor (EGFR)WT and EGFR-vIII in U87 and CAS-1 cells, respectively. Collectively, our findings demonstrate that all tested compounds are able to counteract GBM survival, further supporting the role of SI306 as progenitor of promising new drugs to treat malignant GBM. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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13 pages, 2097 KiB  
Article
Choline Kinase α Inhibitors MN58b and RSM932A Enhances the Antitumor Response to Cisplatin in Lung Tumor Cells
by Juan Carlos Lacal, Rosario Perona, Javier de Castro and Arancha Cebrián
Pharmaceutics 2022, 14(6), 1143; https://doi.org/10.3390/pharmaceutics14061143 - 27 May 2022
Viewed by 1569
Abstract
Lung cancer is one of the main causes of death in developed countries, and non-small cell lung cancer (NSCLC) is the most frequent type (80% of patients). In advanced NSCLC, platinum-based chemotherapy is the frontline palliative treatment, but less than 5% of patients [...] Read more.
Lung cancer is one of the main causes of death in developed countries, and non-small cell lung cancer (NSCLC) is the most frequent type (80% of patients). In advanced NSCLC, platinum-based chemotherapy is the frontline palliative treatment, but less than 5% of patients achieve prolonged survival. Immunotherapy has recently been proposed as the standard of care (SoC) as either monotherapy or in combination with chemotherapy for advanced NSCLC. The levels of expression of PD-L1 are the only predictive biomarkers for patient assessment. Although around 30% of patients receiving immunotherapy achieve 5-year survival, a significant number does not benefit from this novel therapeutic approach. Therefore, there is a need for novel strategies to improve clinical outcomes. The expression level of choline kinase α (ChoKα) is increased in a large number of human tumors, including NSCLC tumors, and constitutes an independent prognostic factor for early-stage NSCLC patients. Thus, ChoKα has been postulated as a new target drug in cancer therapy. The combination of cisplatin with novel targeted drugs such as choline kinase inhibitors may improve both the survival rates and the quality of life of NSCLC patients and may serve as the basis for the development of new therapeutic approaches. To that aim, we developed several in vitro and in vivo approaches to assess the antitumor activity of a novel combination regimen using cisplatin and ChoKα inhibitors. Our results suggest that a proper combination of specific inhibitors of the NSCLC prognostic factor ChoKα and platinum-based conventional chemotherapy might constitute a new, efficient treatment approach for NSCLC patients. This novel approach may help reduce the toxicity profile associated with cisplatin since, despite the advances in NSCLC management in recent years, the overall 5-year survival rate is still poor. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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Review

Jump to: Research

17 pages, 796 KiB  
Review
Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma
by Jieun Bang, Mihyeon Jun, Soyun Lee, Hyuk Moon and Simon Weonsang Ro
Pharmaceutics 2023, 15(8), 2130; https://doi.org/10.3390/pharmaceutics15082130 - 14 Aug 2023
Cited by 4 | Viewed by 1591
Abstract
Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways [...] Read more.
Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/AKT/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we explore recent advancements in understanding the role of the EGFR/PI3K/AKT/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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16 pages, 1881 KiB  
Review
Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)
by Ana Monfort-Vengut and Guillermo de Cárcer
Pharmaceutics 2023, 15(4), 1232; https://doi.org/10.3390/pharmaceutics15041232 - 13 Apr 2023
Cited by 2 | Viewed by 2070
Abstract
Rigosertib (ON-01910.Na) is a small-molecule member of the novel synthetic benzyl-styryl-sulfonate family. It is currently in phase III clinical trials for several myelodysplastic syndromes and leukemias and is therefore close to clinical translation. The clinical progress of rigosertib has been hampered by a [...] Read more.
Rigosertib (ON-01910.Na) is a small-molecule member of the novel synthetic benzyl-styryl-sulfonate family. It is currently in phase III clinical trials for several myelodysplastic syndromes and leukemias and is therefore close to clinical translation. The clinical progress of rigosertib has been hampered by a lack of understanding of its mechanism of action, as it is currently considered a multi-target inhibitor. Rigosertib was first described as an inhibitor of the mitotic master regulator Polo-like kinase 1 (Plk1). However, in recent years, some studies have shown that rigosertib may also interact with the PI3K/Akt pathway, act as a Ras–Raf binding mimetic (altering the Ras signaling pathway), as a microtubule destabilizing agent, or as an activator of a stress-induced phospho-regulatory circuit that ultimately hyperphosphorylates and inactivates Ras signaling effectors. Understanding the mechanism of action of rigosertib has potential clinical implications worth exploring, as it may help to tailor cancer therapies and improve patient outcomes. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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23 pages, 2077 KiB  
Review
Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging
by Andrea Rodríguez-Agustín, Víctor Casanova, Judith Grau-Expósito, Sonsoles Sánchez-Palomino, José Alcamí and Núria Climent
Pharmaceutics 2023, 15(3), 917; https://doi.org/10.3390/pharmaceutics15030917 - 11 Mar 2023
Cited by 3 | Viewed by 4036
Abstract
Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. [...] Read more.
Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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87 pages, 4906 KiB  
Review
Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
by Marina Ferreira Candido, Mariana Medeiros, Luciana Chain Veronez, David Bastos, Karla Laissa Oliveira, Julia Alejandra Pezuk, Elvis Terci Valera and María Sol Brassesco
Pharmaceutics 2023, 15(2), 664; https://doi.org/10.3390/pharmaceutics15020664 - 16 Feb 2023
Cited by 3 | Viewed by 2865
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and [...] Read more.
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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25 pages, 6266 KiB  
Review
Heterocyclic Compounds as Hsp90 Inhibitors: A Perspective on Anticancer Applications
by Mina Ardestani, Zahra Khorsandi, Fariba Keshavarzipour, Siavash Iravani, Hojjat Sadeghi-Aliabadi and Rajender S. Varma
Pharmaceutics 2022, 14(10), 2220; https://doi.org/10.3390/pharmaceutics14102220 - 18 Oct 2022
Cited by 5 | Viewed by 2220
Abstract
Heat shock proteins (Hsps) have garnered special attention in cancer therapy as molecular chaperones with regulatory/mediatory effects on folding, maintenance/stability, maturation, and conformation of proteins as well as their effects on prevention of protein aggregation. Hsp90 ensures the stability of various client proteins [...] Read more.
Heat shock proteins (Hsps) have garnered special attention in cancer therapy as molecular chaperones with regulatory/mediatory effects on folding, maintenance/stability, maturation, and conformation of proteins as well as their effects on prevention of protein aggregation. Hsp90 ensures the stability of various client proteins needed for the growth of cells or the survival of tumor cells; therefore, they are overexpressed in tumor cells and play key roles in carcinogenesis. Accordingly, Hsp90 inhibitors are recognized as attractive therapeutic agents for investigations pertaining to tumor suppression. Natural Hsp90 inhibitors comprising geldanamycin (GM), reclaimed analogs of GM including 17-AAG and DMAG, and radicicol, a natural macrocyclic antifungal, are among the first potent Hsp90 inhibitors. Herein, recently synthesized heterocyclic compounds recognized as potent Hsp90 inhibitors are reviewed along with the anticancer effects of heterocyclic compounds, comprising purine, pyrazole, triazine, quinolines, coumarin, and isoxazoles molecules. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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16 pages, 1129 KiB  
Review
Kinase Inhibition in Multiple Myeloma: Current Scenario and Clinical Perspectives
by Igor Valentim Barreto, Caio Bezerra Machado, Davi Benevides Almeida, Flávia Melo Cunha de Pinho Pessoa, Renan Brito Gadelha, Laudreísa da Costa Pantoja, Deivide de Sousa Oliveira, Rodrigo Monteiro Ribeiro, Germison Silva Lopes, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, André Salim Khayat, Edivaldo Herculano Correa de Oliveira and Caroline Aquino Moreira-Nunes
Pharmaceutics 2022, 14(9), 1784; https://doi.org/10.3390/pharmaceutics14091784 - 25 Aug 2022
Cited by 2 | Viewed by 2100
Abstract
Multiple myeloma (MM) is a blood cell neoplasm characterized by excessive production of malignant monoclonal plasma cells (activated B lymphocytes) by the bone marrow, which end up synthesizing antibodies or antibody fragments, called M proteins, in excess. The accumulation of this production, both [...] Read more.
Multiple myeloma (MM) is a blood cell neoplasm characterized by excessive production of malignant monoclonal plasma cells (activated B lymphocytes) by the bone marrow, which end up synthesizing antibodies or antibody fragments, called M proteins, in excess. The accumulation of this production, both cells themselves and of the immunoglobulins, causes a series of problems for the patient, of a systemic and local nature, such as blood hyperviscosity, renal failure, anemia, bone lesions, and infections due to compromised immunity. MM is the third most common hematological neoplasm, constituting 1% of all cancer cases, and is a disease that is difficult to treat, still being considered an incurable disease. The treatments currently available cannot cure the patient, but only extend their lifespan, and the main and most effective alternative is autologous hematopoietic stem cell transplantation, but not every patient is eligible, often due to age and pre-existing comorbidities. In this context, the search for new therapies that can bring better results to patients is of utmost importance. Protein tyrosine kinases (PTKs) are involved in several biological processes, such as cell growth regulation and proliferation, thus, mutations that affect their functionality can have a great impact on crucial molecular pathways in the cells, leading to tumorigenesis. In the past couple of decades, the use of small-molecule inhibitors, which include tyrosine kinase inhibitors (TKIs), has been a hallmark in the treatment of hematological malignancies, and MM patients may also benefit from TKI-based treatment strategies. In this review, we seek to understand the applicability of TKIs used in MM clinical trials in the last 10 years. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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63 pages, 32074 KiB  
Review
A Comprehensive Overview of Globally Approved JAK Inhibitors
by Ahmed M. Shawky, Faisal A. Almalki, Ashraf N. Abdalla, Ahmed H. Abdelazeem and Ahmed M. Gouda
Pharmaceutics 2022, 14(5), 1001; https://doi.org/10.3390/pharmaceutics14051001 - 06 May 2022
Cited by 79 | Viewed by 10612
Abstract
Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer [...] Read more.
Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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