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Trends in kinase drug discovery: targets, indications and inhibitor design

An Author Correction to this article was published on 02 September 2021

This article has been updated

Abstract

The FDA approval of imatinib in 2001 was a breakthrough in molecularly targeted cancer therapy and heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. Twenty years on, this article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. There are currently 71 small-molecule kinase inhibitors (SMKIs) approved by the FDA and an additional 16 SMKIs approved by other regulatory agencies. Although oncology is still the predominant area for their application, there have been important approvals for indications such as rheumatoid arthritis, and one-third of the SMKIs in clinical development address disorders beyond oncology. Information on clinical trials of SMKIs reveals that approximately 110 novel kinases are currently being explored as targets, which together with the approximately 45 targets of approved kinase inhibitors represent only about 30% of the human kinome, indicating that there are still substantial unexplored opportunities for this drug class. We also discuss trends in kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors and chemical degraders.

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Fig. 1: Timeline of approved kinase inhibitors.
Fig. 2: FDA-approved kinase inhibitors mapped onto the human kinome.
Fig. 3: Structural features of the kinase catalytic domain and inhibitor binding modes.
Fig. 4: Chemical scaffolds used in approved kinase inhibitors.
Fig. 5: Schematic representation of kinase inhibitor binding modes.
Fig. 6: Exploring the kinome.
Fig. 7: Disease indications of kinase-targeting agents in clinical trials.

Data availability

Data are provided in the Supplementary information. Supplementary Table 1 provides information on protein kinase inhibitors approved by selected regulatory agencies (FDA, EMA, NMPA, PMDA and MFDS) and their primary therapeutic targets. Supplementary Table 2 provides information on agents in clinical trials that target protein kinase signalling pathways. Supplementary Table 3 provides success rates of FDA-approved small-molecule kinase inhibitors in clinical trials. Supplementary Table 4 provides information on kinase targets for which modulators in clinical trials are presumed discontinued. Supplementary Table 5 provides information on chemical probes and historical compounds for kinases. Supplementary Fig. 1 provides information on active and not active small-molecule kinase inhibitors targeting established and novel kinases.

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Acknowledgements

H.B.S. was supported by the Swedish Research Council, the Novo Nordisk Foundation and the Swedish Cancer Foundation. M.M.A. received support from the E. and O. Börjesons Foundation. S.K. acknowledges funding by the SGC, a registered charity that receives funds from AbbVie, Bayer, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute (OGI-196), EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510], Janssen, Merck KGaA (also known as EMD in Canada and the US), Merck & Co. (also known as MSD outside Canada and the USA), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome and the Frankfurt Cancer Institute, as well as the German translational cancer network (DKTK). The authors would like to thank E. Faccenda of IUPHAR Guide to Pharmacology for her invaluable help with curating the kinase inhibitors.

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Correspondence to Helgi B. Schiöth.

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D.F. is employed by Cellestia Biotech. Cellestia Biotech had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results. The other authors declare no competing interests.

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Supplementary information

Glossary

Eukaryotic protein kinases

(ePKs). There are eight main groups of eukaryotic protein kinases: AGC (protein kinase A, G and C); CaMK (calcium/calmodulin-dependent kinases); CMGC (cyclin-dependent kinases, MAP kinases, glycogen synthase kinases, CDC-like kinases); TK (tyrosine kinases); STE (homologues of sterile 7); CK1 (casein kinases); TKL (tyrosine kinase like); and the RGC (receptor guanylate cyclase) groups.

Molecular glues

In the context of targeted protein degradation, molecular glues are small molecules that induce association of ubiquitin ligases with their target via monovalent interactions. However, designing a small molecule that can bind to both a ubiquitin ligase and a kinase in this way is highly challenging, and so molecular glues are most often identified by screening compound libraries.

Proteolysis-targeting chimeras

(PROTACs). Bivalent macromolecules composed of a flexible linker that is capped with protein-binding moieties designed to bring ubiquitin ligases and a target such as the kinase of interest into close proximity to promote its degradation. Although this strategy could enable more specific targeting of a given kinase, the large molecular size of PROTACs may pose challenges related to drug characteristics such as oral bioavailability.

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Attwood, M.M., Fabbro, D., Sokolov, A.V. et al. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov 20, 839–861 (2021). https://doi.org/10.1038/s41573-021-00252-y

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