Hot Topics: Trends in kinase drug discovery: twenty years of successfully targeting the kinome

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. Continued advances in the molecular understanding of cancer, multiple approaches to drug design, and the increasing number of resolved kinase structures (1) have facilitated the development of kinase inhibitors with improved potency, selectivity, and efficacy.

Two new analyses published in Nature Reviews Drug Discovery present the historical development of kinase inhibitors as well as the current outlook on kinase drug discovery. Cohen et al. (1) present a detailed study on FDA-approved small molecular weight kinase inhibitors titled Kinase drug discovery 20 years after imatinib: progress and future directions. The analysis encompasses the pivotal events in kinase inhibitor development and remarkable progress made over the past 20 years in improving the potency and specificity of small molecule kinase inhibitors (SMKIs) and the kinase pathways targeted in drug discovery. Importantly, the development of drug resistance to kinase inhibitors and how these challenges are being met in the future of kinase drug discovery are discussed.

The new analysis Trends in kinase drug discovery: targets, indications and inhibitor design published this month by Attwood et al. (2) analyses the landscape of approved and investigational therapies targeting kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. Furthermore, strategies for kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors, and chemical degraders are discussed. Since the approval of fasudil in 1995, the number of approved kinase inhibitors worldwide as increased to 98 drugs, of which 71 are SMKIs and 10 monoclonal antibodies approved by the FDA. Remarkably, the number of FDA-approved SMKIs has more than doubled in the past five years and they constitute ~15% of all novel drug approvals by the FDA. While 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. Nearly 600 investigational kinase-targeting agents that were registered in were included this analysis, consisting of 475 novel SMKIs and 124 biological agents. Information on clinical trials of SMKIs reveals that ~110 novel kinases are currently being explored as targets, which together with the ~45 targets of approved kinase inhibitors represent only ~30% of the human kinome (4), indicating that there are still substantial unexplored opportunities for this drug class.

In summary, although there have been substantial advances in kinase drug discovery, there are still many challenges and opportunities in this field. The potential for developing novel types of kinase inhibitors is large and it is expected that this will continue to be a major area of growth in the next 20 years.

Comments by Misty Attwood and Helgi SchiöthUniversity of Uppsala, Uppsala, Sweden. Helgi Schiöth is Chair for NC-IUPHAR Subcommitees for Melanocortin receptors and Prolactin-releasing peptide receptor. Twitter: @FunctPharm

  1. Structural Genomics Consortium (SGC):
  2. Cohen, P., Cross, D. & Jänne, P.A. Kinase drug discovery 20 years after imatinib: progress and future directions. Nat Rev Drug Discov 20, 551–569 (2021). [PMID: 34002056]
  3. Attwood, M. M., Fabbro, D., Sokolov, A. V., Knapp, S., Schiöth, H. B. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. In press (2021). [PMID: 34354255]
  4. IUPHAR Guide to Pharmacology:

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