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Novel Chemical Tools for Targeted Cancer Therapy
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Novel Chemical Tools for Targeted Cancer Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 10058

Special Issue Editor

Dr. Alexander Shtil

E-Mail Website
Guest Editor
Blokhin Cancer Center and Institute of Gene Biology, Russian Academy of Sciences, 24 Kashirskoye Shosse, 115478 Moscow, Russia
Interests: intracellular signaling; cancer; chemotherapy; molecular targets; drug design; computational chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Intracellular signaling, a language understandable by biological structures, is an astonishingly smart system of cues and responses. Throughout the entire life span this language remains the major source of communication between the organism and the surrounding milieu, between the cells within the tissue, and between the molecules in the cells. Moreover, disease as a sustained deregulation of signaling can be considered a misspelling and misunderstanding.

To expand our knowledge about signaling the researchers need instruments that selectively interact with individual cellular targets. Calling these instruments the exogenous cues we expect the specific cellular replies. Therapeutically speaking, our instruments represent the mechanism-based drug candidates.

I am pleased to propose a Special Issue entitled "Chemical Tools for Targeted Cancer Therapy". I foresee this volume as a compendium of novel trends in chemistry and biology of antitumor agents (mostly, but not exclusively, low molecular weight compounds). New and established targets will be evaluated from the perspective of engagement by chemical instruments. Therefore studies of in silico and experimental interactions of drug candidates with tentative or established targets are welcome. Most importantly, what are the results of these interactions at the subcellular and cellular levels and in the clinic? Finally, of the exceptional value is critical re-evaluation of targeted anticancer treatment via dissection of this concept’s pros and contras.

Dr. Alexander Shtil
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • intracellular signaling
  • cancer
  • chemotherapy
  • molecular targets
  • drug design
  • computational chemistry

Published Papers (6 papers)

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Research

15 pages, 3212 KiB  
Article
Dithioethanol (DTE)-Conjugated Deoxyribose Cyclic Dinucleotide Prodrugs (DTE-dCDNs) as STING Agonist
by Zhiqiang Xie, Yuchen Yang, Zhenghua Wang, Dejun Ma and Zhen Xi
Int. J. Mol. Sci. 2024, 25(1), 86; https://doi.org/10.3390/ijms25010086 - 20 Dec 2023
Viewed by 756
Abstract
To improve the chemical regulation on the activity of cyclic dinucleotides (CDNs), we here designed a reduction-responsive dithioethanol (DTE)-based dCDN prodrug 9 (DTE-dCDN). Prodrug 9 improved the cell permeability with the intracellular levels peaking in 2 h in THP-1 cells. Under the reductive [...] Read more.
To improve the chemical regulation on the activity of cyclic dinucleotides (CDNs), we here designed a reduction-responsive dithioethanol (DTE)-based dCDN prodrug 9 (DTE-dCDN). Prodrug 9 improved the cell permeability with the intracellular levels peaking in 2 h in THP-1 cells. Under the reductive substance such as GSH or DTT, prodrug 9 could be quickly decomposed in 30 min to release the parent dCDN. In THP1-Lucia cells, prodrug 9 also retained a high bioactivity with the EC50 of 0.96 μM, which was 51-, 43-, and 3-fold more than the 2′,3′-cGAMP (EC50 = 48.6 μM), the parent compound 3′,3′-c-di-dAMP (EC50 = 41.3 μM), and ADU-S100 (EC50 = 2.9 μM). The high bioactivity of prodrug 9 was validated to be highly correlated with the activation of the STING signaling pathway. Furthermore, prodrug 9 could also improve the transcriptional expression levels of IFN-β, CXCL10, IL-6, and TNF-α in THP-1 cells. These results will be helpful to the development of chemically controllable CDN prodrugs with a high cellular permeability and potency. Full article
(This article belongs to the Special Issue Novel Chemical Tools for Targeted Cancer Therapy)
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20 pages, 6362 KiB  
Article
New Derivatives of N-Hydroxybutanamide: Preparation, MMP Inhibition, Cytotoxicity, and Antitumor Activity
by Anastasia Balakina, Svyatoslav Gadomsky, Tatyana Kokovina, Tatyana Sashenkova, Denis Mishchenko and Alexei Terentiev
Int. J. Mol. Sci. 2023, 24(22), 16360; https://doi.org/10.3390/ijms242216360 - 15 Nov 2023
Viewed by 806
Abstract
Using a novel method of N-substituted succinimide ring opening, new N-hydroxybutanamide derivatives were synthesized. These compounds were evaluated for their ability to inhibit matrix metalloproteinases (MMPs) and their cytotoxicity. The iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide showed the [...] Read more.
Using a novel method of N-substituted succinimide ring opening, new N-hydroxybutanamide derivatives were synthesized. These compounds were evaluated for their ability to inhibit matrix metalloproteinases (MMPs) and their cytotoxicity. The iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide showed the inhibition of MMP-2, MMP-9, and MMP-14 with an IC50 of 1–1.5 μM. All the compounds exhibited low toxicity towards carcinoma cell lines HeLa and HepG2. The iodoaniline derivative was also slightly toxic to glioma cell lines A-172 and U-251 MG. Non-cancerous FetMSC and Vero cells were found to be the least sensitive to all the compounds. In vivo studies demonstrated that the iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide had low acute toxicity. In a mouse model of B16 melanoma, this compound showed both antitumor and antimetastatic effects, with a 61.5% inhibition of tumor growth and an 88.6% inhibition of metastasis. Our findings suggest that the iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide has potential as a lead structure for the development of new MMP inhibitors. Our new synthetic approach can be a cost-effective method for the synthesis of inhibitors of metalloenzymes with promising antitumor potential. Full article
(This article belongs to the Special Issue Novel Chemical Tools for Targeted Cancer Therapy)
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18 pages, 4464 KiB  
Article
Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors
by Haizhen A. Zhong and Suliman Almahmoud
Int. J. Mol. Sci. 2023, 24(7), 6023; https://doi.org/10.3390/ijms24076023 - 23 Mar 2023
Cited by 11 | Viewed by 1963
Abstract
The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the [...] Read more.
The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the subtype selectivity of and the mutational effects on inhibitor binding. We also compared the Covalent Dock programs from the Schrodinger software suite and the MOE software suite to determine which method to use for the drug design of covalent inhibitors. Our results showed that the docking affinity from 4Z16 (JAK3 wild-type model), 4E4N (JAK1), 4D1S (JAK2), and 7UYT (TYK2) from the Schrödinger software suite agreed well with the experimentally derived binding free energies with small predicted mean errors. However, the data from the mutant 5TTV model using the Schrödinger software suite yielded relatively large mean errors, whereas the MOE Covalent Dock program gave small mean errors in both the wild-type and mutant models for our model proteins. The docking data revealed that Leu905 of JAK3 and the hydrophobic residue at the same position in different subtypes (Leu959 of JAK1, Leu932 of JAK2, and Val981 of TYK2) is important for ligand binding to the JAK proteins. Arg911 and Asp912 of JAK3, Asp939 of JAK2, and Asp988 of TYK2 can be used for selective binding over JAK1, which contains Lys965 and Glu966 at the respective positions. Asp1021, Asp1039, and Asp1042 can be utilized for JAK1-selective ligand design, whereas Arg901 and Val981 may help guide TYK2-selective molecule design. Full article
(This article belongs to the Special Issue Novel Chemical Tools for Targeted Cancer Therapy)
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12 pages, 9276 KiB  
Article
New Transcriptomic Biomarkers of 5-Fluorouracil Resistance
by János Tibor Fekete and Balázs Győrffy
Int. J. Mol. Sci. 2023, 24(2), 1508; https://doi.org/10.3390/ijms24021508 - 12 Jan 2023
Cited by 3 | Viewed by 1898
Abstract
The overall response rate to fluoropyrimidine monotherapy in colorectal cancer (CRC) is limited. Transcriptomic datasets of CRC patients treated with 5-fluorouracil (5FU) could assist in the identification of clinically useful biomarkers. In this research, we aimed to analyze transcriptomic cohorts of 5FU-treated cell [...] Read more.
The overall response rate to fluoropyrimidine monotherapy in colorectal cancer (CRC) is limited. Transcriptomic datasets of CRC patients treated with 5-fluorouracil (5FU) could assist in the identification of clinically useful biomarkers. In this research, we aimed to analyze transcriptomic cohorts of 5FU-treated cell lines to uncover new predictive biomarker candidates and to validate the strongest hits in 5FU-treated human colorectal cancer samples with available clinical response data. We utilized an in vitro dataset of cancer cell lines treated with 5FU and used the reported area under the dose–response curve values to determine the therapeutic response to 5FU treatment. Mann–Whitney and ROC analyses were performed to identify significant genes. The strongest genes were combined into a single signature using a random forest classifier. The compound 5-fluorouracil was tested in 592 cell lines (294 nonresponders and 298 responders). The validation cohort consisted of 157 patient samples with 5FU monotherapy from three datasets. The three strongest associations with treatment outcome were observed in SHISA4 (AUC = 0.745, p-value = 5.5 × 10−25), SLC38A6 (AUC = 0.725, p-value = 3.1 × 10−21), and LAPTM4A (AUC = 0.723, p-value = 6.4 × 10−21). A random forest model utilizing the top genes reached an AUC value of 0.74 for predicting therapeutic sensitivity. The model correctly identified 83% of the nonresponder and 73% of the responder patients. The cell line cohort is available and the entire human colorectal cohort have been added to the ROCPlot analysis platform. Here, by using in vitro and in vivo data, we present a framework enabling the ranking of future biomarker candidates of 5FU resistance. A future option is to conduct an independent validation of the established predictors of resistance. Full article
(This article belongs to the Special Issue Novel Chemical Tools for Targeted Cancer Therapy)
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29 pages, 5379 KiB  
Article
Identifying Drug Targets of Oral Squamous Cell Carcinoma through a Systems Biology Method and Genome-Wide Microarray Data for Drug Discovery by Deep Learning and Drug Design Specifications
by Yi-Chung Lin and Bor-Sen Chen
Int. J. Mol. Sci. 2022, 23(18), 10409; https://doi.org/10.3390/ijms231810409 - 8 Sep 2022
Cited by 8 | Viewed by 2327
Abstract
In this study, we provide a systems biology method to investigate the carcinogenic mechanism of oral squamous cell carcinoma (OSCC) in order to identify some important biomarkers as drug targets. Further, a systematic drug discovery method with a deep neural network (DNN)-based drug–target [...] Read more.
In this study, we provide a systems biology method to investigate the carcinogenic mechanism of oral squamous cell carcinoma (OSCC) in order to identify some important biomarkers as drug targets. Further, a systematic drug discovery method with a deep neural network (DNN)-based drug–target interaction (DTI) model and drug design specifications is proposed to design a potential multiple-molecule drug for the medical treatment of OSCC before clinical trials. First, we use big database mining to construct the candidate genome-wide genetic and epigenetic network (GWGEN) including a protein–protein interaction network (PPIN) and a gene regulatory network (GRN) for OSCC and non-OSCC. In the next step, real GWGENs are identified for OSCC and non-OSCC by system identification and system order detection methods based on the OSCC and non-OSCC microarray data, respectively. Then, the principal network projection (PNP) method was used to extract core GWGENs of OSCC and non-OSCC from real GWGENs of OSCC and non-OSCC, respectively. Afterward, core signaling pathways were constructed through the annotation of KEGG pathways, and then the carcinogenic mechanism of OSCC was investigated by comparing the core signal pathways and their downstream abnormal cellular functions of OSCC and non-OSCC. Consequently, HES1, TCF, NF-κB and SP1 are identified as significant biomarkers of OSCC. In order to discover multiple molecular drugs for these significant biomarkers (drug targets) of the carcinogenic mechanism of OSCC, we trained a DNN-based drug–target interaction (DTI) model by DTI databases to predict candidate drugs for these significant biomarkers. Finally, drug design specifications such as adequate drug regulation ability, low toxicity and high sensitivity are employed to filter out the appropriate molecular drugs metformin, gefitinib and gallic-acid to combine as a potential multiple-molecule drug for the therapeutic treatment of OSCC. Full article
(This article belongs to the Special Issue Novel Chemical Tools for Targeted Cancer Therapy)
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14 pages, 2797 KiB  
Article
Differential Impact of Random GC Tetrad Binding and Chromatin Events on Transcriptional Inhibition by Olivomycin A
by Alexandra K. Isagulieva, Dmitry N. Kaluzhny, Artemy D. Beniaminov, Nataliya V. Soshnikova and Alexander A. Shtil
Int. J. Mol. Sci. 2022, 23(16), 8871; https://doi.org/10.3390/ijms23168871 - 9 Aug 2022
Viewed by 1590
Abstract
Olivomycin A (OA), an antibiotic of the aureolic acid family, interferes with gene transcription upon forming complexes with GC-rich regions in the DNA minor groove. We demonstrate that the mechanism of transcriptional deregulation is not limited to OA interaction with GC-containing binding sites [...] Read more.
Olivomycin A (OA), an antibiotic of the aureolic acid family, interferes with gene transcription upon forming complexes with GC-rich regions in the DNA minor groove. We demonstrate that the mechanism of transcriptional deregulation is not limited to OA interaction with GC-containing binding sites for transcription factors. Using electrophoretic mobility shift assays and DNAse I footprinting of cytomegalovirus (CMV) promoter fragments carrying OA-preferred GC tetrads (CMVwt), we showed OA binding specifically to GC islands. Replacement of G for A in these tetrads (CMVmut) abrogated OA binding. Furthermore, OA decreased RNA polymerase II (RNAPII) binding to the CMVwt promoter and inhibited the reporter gene expression. In line with the absence of OA binding sites in CMVmut DNA, the expression driven from this promoter was weakly sensitive to OA. In the endogenous genes OA decreased RNAPII on promoters and coding regions. In certain cases this phenomenon was concomitant with the increased histone 3 abundance. However, the sensitivity to OA did not correlate with GC patterns around transcription start sites, suggesting that certain GC stretches play unequal roles in OA-induced transcriptional perturbations. Thus, OA affects transcription via complex mechanisms in which GC tetranucleotide binding causes RNAPII/chromatin alterations differentially manifested in individual gene contexts. Full article
(This article belongs to the Special Issue Novel Chemical Tools for Targeted Cancer Therapy)
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