Aug 2026· Chimia (Basel)· Vol 80 7-8, pp.
501-508
· 0 citations· 4 references
Medicine
TL;DR
Together, these examples define an expanding pharmacological vocabulary for kinase drug discovery: one that asks not only whether a molecule inhibits its target kinase, but how ligand binding rewires protein stability, interactions, localisation, and function.
Abstract
Kinase inhibitors are a cornerstone of modern drug discovery, with more than 100 approved compounds which have had a transformative impact in precision oncology and inflammatory disease. Their success has rested largely on small-molecule control of catalytic activity through ATP-site engagement; a framework that leaves important biology unaddressed, including non-catalytic kinase functions, resistance driven by active-site mutation, and the limits of selectivity imposed by pocket conservation. Against this backdrop, the observation that kinase inhibitors can reduce target protein abundance has gained new mechanistic depth. Chaperone deprivation, supercharging of native degradation circuits, and context-dependent mutant-selective depletion mark distinct routes through which inhibitor binding can intersect with cellular proteostasis. The kinase inhibitor CR8 extends this logic into chemically encoded degradation: CR8 acts as a molecular glue degrader by creating, within the ligand-bound kinase complex, a composite surface that directly recruits a ubiquitin ligase, resulting in cyclin K degradation. Thalidomide analogues can degrade kinases through scaffolds that do not bind the kinase in isolation: ligase-binding compounds that recruit neosubstrate kinases through recognition of structural surface degrons. Deliberately engineered PROTACs encode ligase-target proximity through heterobifunctional architecture to convert kinase binders into degraders. Beyond degradation, induced-proximity mechanisms - from the clinically established rapamycin to bifunctional molecules that redirect kinase activity or restrict inhibition to tumour cells - show how small molecules can reshape kinase interaction states rather than simply block active sites. Together, these examples define an expanding pharmacological vocabulary for kinase drug discovery: one that asks not only whether a molecule inhibits its target kinase, but how ligand binding rewires protein stability, interactions, localisation, and function.
The structural and medicinal chemistry principles underlying (i) allosteric inhibition and (ii) proximity-induced degradation are summarized, with an emphasis on design logic, structure-activity relationships, and key liabilities in the beyond rule of five space.
Mei Zhou, Linshan Li, Xiao-Juan Tang et al.· Future Medicinal Chemistry· 0 citations
Members of the DYRK kinase family have been implicated in the regulation of key metabolic processes. In particular, DYRK1B plays a central role in hepatic lipid metabolism and fatty liver disease. Notably, these functions depend not only on the enzyme’s catalytic activity but also on scaffolding properties. Consequently, therapeutic ambitions aiming to target the entire spectrum of DYRK1B functions must inactivate or eliminate the protein itself rather than merely inhibiting its enzymatic activity, as is achieved by current kinase inhibitors. In this study, we describe a small molecule from the leucettinib class of DYRK inhibitors (LCTB-92) that not only suppresses DYRK kinase activity but also promotes selective ablation of the DYRK1B protein while sparing the closely related paralog DYRK1A. The identification of this compound establishes a foundation for the development of selective agents capable of targeting the entire DYRK1B protein scaffold, thereby addressing catalytic-dependent as well as catalytic-independent kinase functions.
Miriam S. Ems, Mattias F. Lindberg, Till Adhikary et al.· ACS Pharmacology & Trans...· 0 citations
Kinases are highly explored drug targets due to their central role in cell growth, differentiation, and cell death, as well as their relationship to cancer initiation and progression. However, with more than 500 kinases in the human kinome and significant structural similarities among them, kinases present a major selectivity challenge. Bruton’s tyrosine kinase (BTK), a highly studied kinase, plays an important role in the B-cell receptor pathway. Overexpression of BTK in B cells has been linked to the development of B-cell lymphomas, like chronic lymphocytic leukemia (CLL), as well as certain autoimmune diseases. For this reason, BTK is an attractive therapeutic target. In this review, we will provide a summary of the design of irreversible inhibitors, reversible inhibitors, and Proteolysis-targeting chimera (PROTAC) degraders targeting BTK. We will include crystal structures of compounds bound to BTKWT and provide a review of how the design of these inhibitors and PROTACs leads to a more selective inhibition and degradation of BTK. With the emergence of identified BTK resistance mutations, alternative strategies beyond established BTK inhibitors are fundamental for designing more selective inhibitors and degraders that can overcome resistance.
Eduardo Bravo, C. C. Pastrana, Erica N Lamkin et al.· Cells· 0 citations
CK2 is a constitutively active serine/threonine kinase implicated in cancer, viral infection, and neurodegeneration, but its conserved ATP-binding site and complex holoenzyme assembly have long made selective inhibition challenging. This Perspective discusses three complementary strategies for selective CK2 inhibition: targeting the CK2α/β interface with small molecules, disrupting the same interface with conformationally constrained peptides, and exploiting the cryptic αD pocket for dual-site inhibitor design. CK2α/β-interface inhibitors, including CAM187, CAM7117 and P8C9, established structurally validated routes to modulate holoenzyme assembly and β-dependent substrate phosphorylation. Validation of the αD pocket as a ligandable cryptosteric site enabled dual-site ligands such as CAM4066 and αD-directed inhibitors such as CAM4712, followed by related advances including AB668, KDX1381 and Biv5. These efforts culminated in APL-5125, a highly selective, subnanomolar dual-site inhibitor now in Phase 1/2 clinical evaluation.
A. Sokhal, S. Krajcovicova, J. Iegre et al.· Journal of Medicinal Chemist...· 0 citations
The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed.
Lauryn Buckley-Benbow, Antonia M. Rout, Andrew B. Fielding et al.· TARGETS· 0 citations
KRAS is one of the most frequently mutated oncogenes in human cancers and plays a central role in regulating signaling pathways that control cell proliferation, survival and metabolism. Recent advances in allele-specific inhibitors, particularly those targeting KRASG12C, have demonstrated that direct pharmacological inhibition of KRAS is clinically feasible. However, the durability of therapeutic responses remains limited due to intrinsic and acquired resistance mechanisms, including secondary KRAS mutations, pathway reactivation and adaptive signaling rewiring. These challenges highlight the need for complementary strategies that extend beyond direct catalytic inhibition. The ubiquitin-proteasome system has emerged as a critical regulator of KRAS stability and signaling networks. Deubiquitinases (DUBs), which reverse ubiquitination and modulate protein turnover, have been increasingly recognized as key regulators of oncogenic signaling pathways upstream and downstream of KRAS. By influencing protein abundance, localization and signaling competence, DUBs can modulate pathway robustness and adaptive responses that contribute to therapeutic resistance. In this Review, we summarize current understanding of ubiquitin-dependent regulation in KRAS-driven cancers, focusing on DUBs and E3 ligases that directly control KRAS stability as well as those that regulate major KRAS effector pathways, including RTK-RAS, RAF-MEK-ERK and PI3K-AKT-mTOR signaling. We further discuss the therapeutic implications of DUB inhibition, its potential to overcome resistance and its relationship to emerging targeted protein degradation strategies.
Yeonjoo Lee, Sua Hwang, Hyungkyung Shin et al.· Experimental and Molecular M...· 0 citations
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