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Kinase drug discovery 20 years after imatinib: progress and future directions

Nature Reviews Drug Discovery volume 20, pages 551–569 (2021)Cite this article

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Abstract

Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we review the remarkable progress made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001. These compounds have had a significant impact on the way in which we now treat cancers and non-cancerous conditions. We discuss how the challenge of drug resistance to kinase inhibitors is being met and the future of kinase drug discovery.

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Fig. 1: Timeline depicting important events in the development and approval of kinase inhibitors over the past 20 years since imatinib was approved for treatment of CML in 2001.
Fig. 2: Mutations in the classical MAP kinase cascade cause cancer.
Fig. 3: Mechanisms that can cause drug resistance.
Fig. 4: Chemical structures of first-generation, second-generation and third-generation EGFR inhibitors.
Fig. 5: Binding modes for first-generation, second-generation and third-generation EGFR inhibitors.

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Acknowledgements

The authors thank R. Ward at AstraZeneca for valuable input, including help in generating Figs. 4 and 5, and R. Marais for valuable discussions.

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Authors and Affiliations

  1. MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK

    Philip Cohen

  2. AstraZeneca, Cambridge, UK

    Darren Cross

  3. Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Harvard University, Boston, MA, USA

    Pasi A. Jänne

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P.C., D.C. and P.J. researched, wrote and edited this Review.

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Correspondence to Philip Cohen, Darren Cross or Pasi A. Jänne.

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P.C. has shares in Alliance Pharma, AstraZeneca and GlaxoSmithKline and is a member of the Scientific Advisory Boards of Mission Therapeutics, Ubiquigent and Biocatalyst International. D.C. is an employee and shareholder of AstraZeneca. P.A.J. has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Takeda Oncology, ACEA Biosciences, Eli Lilly and Company, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, LOXO Oncology, Daiichi Sankyo, Sanofi Oncology, Voronoi, SFJ Pharmaceuticals, Biocartis, Novartis Oncology, Nuvalent, Esai, Bayer, Transcenta and Silicon Therapeutics; receives post-marketing royalties from DFCI-owned intellectual property on EGFR mutations licensed to Lab Corp; has sponsored research agreements with AstraZeneca, Daichi-Sankyo, PUMA, Boehringer-Ingelheim, Eli Lilly and Company, Revolution Medicines, and Astellas Pharmaceuticals; and has stock ownership in Gatekeeper Pharmaceuticals.

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Glossary

Protein kinases

Enzymes that catalyse transfer of the γ-phosphate of ATP to amino acid side chains in substrate proteins, such as serine, threonine and tyrosine residues.

Polypharmacology

A term to describe a feature of kinase inhibitors that can inhibit multiple kinase _targets at clinically achievable concentrations. This feature can lead to a broader range of clinical activity and/or increased toxicity.

Next-generation inhibitor

A kinase inhibitor that is improved sufficiently compared with the original first-generation drug that it is effective in preventing disease progression in patients who are no longer responsive to the original drug.

Bromodomain

(BRD). A particular type of protein domain comprising approximately 110 amino acids that recognizes acetylated lysine residues in other proteins, frequently leading to the remodelling of chromatin and changes in gene transcription. Many drugs initially developed as protein kinase inhibitors also bind to and inhibit the functions of BRDs.

Pseudokinase

Pseudokinases are proteins that possess a domain that closely resembles the catalytic domains of protein kinases, but that lack one or more amino acid residues essential for catalysis by other kinases, and are therefore presumed to be catalytically inactive. Some pseudokinases have subsequently been found to display kinase catalytic activity for interesting reasons or to have acquired entirely novel catalytic functions.

Oncogenic addiction

A process in which cancers with genetic, epigenetic or chromosomal irregularities become dependent on one or a few genes for maintenance and survival. Such cancers can be exquisitely sensitive to killing by particular kinase inhibitors if one of the genes required for cancer survival encodes a particular protein kinase or a regulator of kinase activation.

Blood–brain barrier

(BBB). A highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system.

Acquired drug resistance

Clinical drug resistance, characterized by tumour growth while on treatment, that develops in patients following an initial clinical benefit (a clinical response or prolonged stable disease).

Gatekeeper mutation

The gatekeeper is a conserved amino acid residue near the ATP-binding site that, when occupied by an amino acid with a small side chain (typically threonine), creates a small hydrophobic pocket that is _targeted by many protein kinase inhibitors. The mutation of the gatekeeper to an amino acid with a bulkier side chain fills the hydrophobic pocket, making it inaccessible to the kinase inhibitor, but not ATP. Such mutations are a frequent cause of drug resistance.

Solvent-front mutations

The solvent front is a region of the ATP pocket in the catalytic domain that has a relatively high solvent exposure, and where multiple kinase inhibitors typically make contact. Mutation of residues in this region frequently cause resistance to kinase inhibitors.

Kinase profiling

A technology for assessing which of the 500 plus protein kinases encoded by the human genome is inhibited by a particular kinase inhibitor. Some technologies used for kinase profiling can identify _targets of such drugs that are not protein kinases.

Covalent inhibitors

Kinase inhibitors that bind irreversibly to their _targets, most commonly by making a covalent chemical bond with a cysteine residue of the kinase.

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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). https://doi.org/10.1038/s41573-021-00195-4

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