Issue 23, 2020

PI3K inhibitors: review and new strategies

Abstract

The search is on for effective specific inhibitors for PI3Kα mutants. PI3Kα, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110α catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3Kα signalling is commonly associated with tumorigenesis and drug resistance. Despite its vast importance, only recently the FDA approved the first drug (alpelisib by Novartis) for breast cancer. A second (GDC0077), classified as PI3Kα isoform-specific, is undergoing clinical trials. Not surprisingly, these ATP-competitive drugs commonly elicit severe concentration-dependent side effects. Here we briefly review PI3Kα mutations, focus on PI3K drug repertoire and propose new, to-date unexplored PI3Kα therapeutic strategies. These include (1) an allosteric and orthosteric inhibitor combination and (2) taking advantage of allosteric rescue mutations to guide drug discovery.

Graphical abstract: PI3K inhibitors: review and new strategies

Article information

Article type
Perspective
Submitted
20 mars 2020
Accepted
18 mai 2020
First published
19 mai 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 5855-5865

PI3K inhibitors: review and new strategies

M. Zhang, H. Jang and R. Nussinov, Chem. Sci., 2020, 11, 5855 DOI: 10.1039/D0SC01676D

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