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New Advances in the Development of Kinase Inhibitors

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 19646

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Dr. Ana Ramos

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Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain
Interests: medicinal chemistry; organic synthesis; molecular modelling; PROTACs; MMPs; HDAC; CK2

Dr. José María Zapico

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Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain
Interests: drug design; organic synthesis; fluorescent probes; PET; MMPs; HDAC; CK2

Special Issue Information

Dear Colleagues,

Kinases are a large family of enzymes critical for the regulation of different cellular functions, through the phosphorylation of a large number of substrates. Therefore, they are recognized targets in the development of drugs for the treatment of many pathological conditions.

The global market for kinase inhibitors in 2019 moved more than forty billion dollars and it is expected to continue to grow in the future. More recently, pharmacological inhibition of p38, CK2, CDK, ALX and PIKFYVE has been shown to possess antiviral activity and potential efficacy for the treatment of COVID-19.

Kinases are classified into broad groups by their substrate: protein kinases, lipid kinases and carbohydrate kinases. There are some 500 kinases encoded by the human genome.

Protein kinases can be classified into three groups according to the phosphorylated amino acid: Protein-Tyrosine kinases (PTKs), Serine-threonine protein kinases (STKs) and dual-specificity kinases. Many are validated targets for the development of drugs against cancer, diabetes, inflammatory and degenerative diseases, among others.

Lipid kinases are new classes of potential drug targets. PI-3 and sphingosine kinases regulate a wide variety of cellular functions, including cell growth, proliferation, differentiation, motility, intracellular trafficking, and survival. As a result, defects in lipid kinase function lead to multiple disease states, including several forms of cancer and diabetes.

Carbohydrate kinases are attractive targets for therapeutics, with human glucokinase and galactokinase-1 being of particular interest.

Most kinases are members of the same superfamily, so the question of selectivity is critical. X-Ray crystallography and computational techniques have provided key structural information for the synthesis of more specific inhibitors, including molecules that interact out of the ATP binding site (allosteric inhibitors).

This Special Issue focuses on recent advances in the development of protein inhibitors including allosteric inhibitors, multitarget strategies, PROteolysis-Targeting Chimera (PROTACs), imaging probes (PET and fluorescent), and kinase conjugates for targeted drug delivery.

Dr. Ana Ramos
Dr. José María Zapico
Guest Editors

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Keywords

protein kinases
organic synthesis
drug design
multitarget inhibitors
allosteric inhibition
molecular probes
PROTACs

Published Papers (6 papers)

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Research

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24 pages, 12995 KiB

Open AccessArticle

Molecular Recognition of FDA-Approved Small Molecule Protein Kinase Drugs in Protein Kinases

by Yan Zhu and Xiche Hu

Molecules 2022, 27(20), 7124; https://doi.org/10.3390/molecules27207124 - 21 Oct 2022

Cited by 2 | Viewed by 2010

Abstract

Protein kinases are key enzymes that catalyze the covalent phosphorylation of substrates via the transfer of the γ-phosphate of ATP, playing a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. Due to their pivotal cellular role, the aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Decades of intense development of protein kinase inhibitors (PKIs) resulted in 71 FDA-approved PKI drugs that target dozens of protein kinases for the treatment of various diseases. How do FDA-approved protein kinase inhibitor PKI drugs compete with ATP in their own binding pocket? This is the central question we attempt to address in this work. Based on modes of non-bonded interactions and their calculated interaction strengths by means of the advanced double hybrid DFT method B2PLYP, the molecular recognition of PKI drugs in the ATP-binding pockets was systematically analyzed. It was found that (1) all the FDA-approved PKI drugs studied here form one or more hydrogen bond(s) with the backbone amide N, O atoms in the hinge region of the ATP binding site, mimicking the adenine base; (2) all the FDA-approved PKI drugs feature two or more aromatic rings. The latter reach far and deep into the hydrophobic regions I and II, forming multiple CH-π interactions with aliphatic residues L(3), V(11), A(15), V(36), G(51), L(77) and π-π stacking interactions with aromatic residues F(47) and F(82), but ATP itself does not utilize these regions extensively; (3) all FDA-approved PKI drugs studied here have one thing in common, i.e., they frequently formed non-bonded interactions with a total of 12 residues L(3),V(11), A(15), K(17), E(24),V(36),T(45), F(47), G(51), L(77), D(81) and F(82) in the ATP binding. Many of those 12 commonly involved residues are highly conserved residues with important structural and catalytic functional roles. K(17) and E(24) are the two highly conserved residues crucial for the catalytic function of kinases. D(81) and F(82) belong to the DFG motif; T(45) was dubbed the gate keeper residue. F(47) is located on the hinge region and G(51) sits on the linker that connects the hinge to the αD-helix. It is this targeting of highly conserved residues in protein kinases that led to promiscuous PKI drugs that lack selectivity. Although the formation of hydrogen bond(s) with the backbone of the hinge gives PKI drugs the added binding affinity and the much-needed directionality, selectivity is sacrificed. That is why so many FDA-approved PKI drugs are known to have multiple targets. Moreover, off-target-mediated toxicity caused by a lack of selectivity was one of the major challenges facing the PKI drug discovery community. This work suggests a road map for future PKI drug design, i.e., targeting non-conserved residues in the ATP binding pocket to gain better selectivity so as to avoid off-target-mediated toxicity. Full article

(This article belongs to the Special Issue New Advances in the Development of Kinase Inhibitors)

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12 pages, 3280 KiB

Open AccessArticle

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

by Ghulam Md. Ashraf, Debarati DasGupta, Mohammad Zubair Alam, Saleh S. Baeesa, Badrah S. Alghamdi, Firoz Anwar, Thamer M. A. Alqurashi, Sharaf E. Sharaf, Waleed Al Abdulmonem, Mohammed A. Alyousef, Fahad A. Alhumaydhi and Anas Shamsi

Molecules 2022, 27(14), 4652; https://doi.org/10.3390/molecules27144652 - 21 Jul 2022

Cited by 5 | Viewed by 2248 | Correction

Abstract

Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP’s). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser²⁶² residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer’s disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson’s disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of −6.9 kcal/mol forming interactions with binding pocket’s critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC₅₀ = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 10⁶ M⁻¹. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs. Full article

(This article belongs to the Special Issue New Advances in the Development of Kinase Inhibitors)

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12 pages, 2726 KiB

Open AccessArticle

Effects of Specific Inhibitors for CaMK1D on a Primary Neuron Model for Alzheimer’s Disease

by Paige Grant, Jitendra Kumar, Satyabrata Kar and Michael Overduin

Molecules 2021, 26(24), 7669; https://doi.org/10.3390/molecules26247669 - 18 Dec 2021

Cited by 4 | Viewed by 2769

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD. Full article

(This article belongs to the Special Issue New Advances in the Development of Kinase Inhibitors)

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20 pages, 41845 KiB

Open AccessArticle

ROCK2-Specific Inhibitor KD025 Suppresses Adipocyte Differentiation by Inhibiting Casein Kinase 2

by Nhu Nguyen Quynh Tran and Kwang-Hoon Chun

Molecules 2021, 26(16), 4747; https://doi.org/10.3390/molecules26164747 - 05 Aug 2021

Cited by 13 | Viewed by 2858

Abstract

KD025, a ROCK2 isoform-specific inhibitor, has an anti-adipogenic activity which is not mediated by ROCK2 inhibition. To identify the target, we searched binding targets of KD025 by using the KINOMEscan^TM screening platform, and we identified casein kinase 2 (CK2) as a novel target. KD025 showed comparable binding affinity to CK2α (K_d = 128 nM). By contrast, CK2 inhibitor CX-4945 and ROCK inhibitor fasudil did not show such cross-reactivity. In addition, KD025 effectively inhibited CK2 at a nanomolar concentration (IC₅₀ = 50 nM). We examined if the inhibitory effect of KD025 on adipocyte differentiation is through the inhibition of CK2. Both CX-4945 and KD025 suppressed the generation of lipid droplets and the expression of proadipogenic genes Pparg and Cebpa in 3T3-L1 cells during adipocyte differentiation. Fasudil exerted no significant effect on the quantity of lipid droplets, but another ROCK inhibitor Y-27632 increased the expression of Pparg and Cebpa. Both CX-4945 and KD025 acted specifically in the middle stage (days 1–3) but were ineffective when treated at days 0–1 or the late stages, indicating that CX-4945 and KD025 may regulate the same target, CK2. The mRNA and protein levels of CK2α and CK2β generally decreased in 3T3-L1 cells at day 2 but recovered thereafter. Other well-known CK2 inhibitors DMAT and quinalizarin inhibited effectively the differentiation of 3T3-L1 cells. Taken together, the results of this study confirmed that KD025 inhibits ROCK2 and CK2, and that the inhibitory effect on adipocyte differentiation is through the inhibition of CK2. Full article

(This article belongs to the Special Issue New Advances in the Development of Kinase Inhibitors)

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Review

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24 pages, 2475 KiB

Open AccessReview

Overview of Research into mTOR Inhibitors

by Beibei Mao, Qi Zhang, Li Ma, Dong-Sheng Zhao, Pan Zhao and Peizheng Yan

Molecules 2022, 27(16), 5295; https://doi.org/10.3390/molecules27165295 - 19 Aug 2022

Cited by 33 | Viewed by 5555

Abstract

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance. Full article

(This article belongs to the Special Issue New Advances in the Development of Kinase Inhibitors)

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21 pages, 2085 KiB

Open AccessReview

Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment

by Ni Made Pitri Susanti and Daryono Hadi Tjahjono

Molecules 2021, 26(15), 4462; https://doi.org/10.3390/molecules26154462 - 24 Jul 2021

Cited by 23 | Viewed by 3350

Abstract

In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy’s effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer. Full article

(This article belongs to the Special Issue New Advances in the Development of Kinase Inhibitors)

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