Kinase inhibitors: the road ahead

Abstract

Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.

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Figure 1: Kinase inhibitors in diverse biological processes and new therapeutic areas.
Figure 2: Opportunities for modulating transcription via inhibition of kinases in the basal transcriptional machinery.
Figure 3: US Food and Drug Administration-approved kinase inhibitors for oncology and non-oncology indications (autoimmune and inflammatory disease) over time.
Figure 4: Chemical methods of inducing kinase degradation.

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Acknowledgements

The authors thank B.J. Pinch, D.A. Scott, N.P. Kwiatkowski and C.M. Olson for proofreading and comments.

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Correspondence to Nathanael S. Gray.

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N.S.G. is a scientific founder and equity holder in C4, Petra, Syros and Gatekeeper Pharmaceuticals.

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Glossary

Free-energy perturbation

(FEP). A method for computing free-energy differences from molecular dynamics simulations on the basis of statistical mechanics.

Super-enhancers

(SEs). Large clusters of transcriptional enhancers, which normally drive expression of genes that define cell identity. Tumour cells acquire SEs at oncogenes and at genes associated with the acquisition of the hallmarks of cancer.

Tumour microenvironment

The cellular environment in which the tumour exists, which is composed of surrounding blood vessels, immune cells, fibroblasts, inflammatory cells, lymphocytes, signalling molecules and the extracellular matrix. The tumour microenvironment and the tumour are constantly interacting; thus, the tumour microenvironment affects tumour development and progression.

T cell checkpoint inhibitors

Antibody-based therapies that block inhibitory pathways that regulate the adaptive immune response. Currently approved T cell checkpoint inhibitors target programmed cell death protein 1 (PD1), PDL1 (PD1 ligand 1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4).

Natural killer cells

Lymphocytes able to bind to certain tumour cells and virus-infected cells and kill them by the injection of granzymes. Unlike T cells, natural killer cells can recognize stressed cells in the absence of antibodies or major histocompatibility complex (MHC) expression, and elicit rapid immune responses.

PROTACs

Proteolysis-targeting chimaeras (PROTACs) are two-headed molecules capable of removing unwanted proteins by inducing selective intracellular proteolysis through induction of their ubiquitylation.

Covalent kinase inhibitors

Kinase inhibitors that contain a weakly reactive electrophile. Upon a reversible binding interaction, the electrophilic warhead is brought into close proximity with a nucleophilic residue in the kinase, often cysteine, which subsequently reacts to form a covalently bonded complex.

DNA-encoded library

Contains small molecules conjugated to short DNA fragments that serve as identification barcodes. The technique enables the mass interrogation of chemical libraries via affinity selection, typically on an immobilized protein target, followed by amplification of the binder's 'barcodes' via PCR and compound identification by DNA sequencing. The advantage of this technique is its screening efficiency.

Alchemical pathways

Simulated pathways from one physical state to another, that proceed via a series of non-physical intermediates.

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Ferguson, F., Gray, N. Kinase inhibitors: the road ahead. Nat Rev Drug Discov 17, 353–377 (2018). https://doi.org/10.1038/nrd.2018.21

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