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Protein kinase inhibitors: Insights into drug design from structure

Lookup NU author(s): Professor Martin NobleORCiD, Professor Jane Endicott

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Abstract

Protein kinases are targets for treatment of a number of diseases. This review focuses on kinase inhibitors that are in the clinic or in clinical trials and for which structural information is available. Structures have informed drug design and have illuminated the mechanism of inhibition. We review progress with the receptor tyrosine kinases (growth factor receptors EGFR, VEGFR, and FGFR) and nonreceptor tyrosine kinases (Bcr-Abl), where advances have been made with cancer therapeutic agents such as Herceptin and Gleevec. Among the serine-threonine kinases, p38, Rho-kinase, cyclin-dependent kinases, and Chk1 have been targeted with productive results for inflammation and cancer. Structures have provided insights into targeting the inactive or active form of the kinase, for targeting the global constellation of residues at the ATP site or less conserved additional pockets or single residues, and into targeting noncatalytic domains.

Publication metadata

Author(s): Noble MEM; Endicott JA; Johnson LN

Publication type: Review

Publication status: Published

Journal: Science

Year: 2004

Volume: 303

Issue: 5665

Pages: 1800-1805

ISSN (print): 0036-8075

ISSN (electronic): 1095-9203

Publisher: AMER ASSOC ADVANCEMENT SCIENCE

URL: http://dx.doi.org/10.1126/science.1095920

DOI: 10.1126/science.1095920

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