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Issue 23, 2020
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PI3K inhibitors: review and new strategies

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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

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Article information


Submitted
20 Mar 2020
Accepted
18 May 2020
First published
19 May 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 5855-5865
Article type
Perspective

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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    [Original citation] - Published by The Royal Society of Chemistry.

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