PI3K inhibitors: Review and new strategies

Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov*, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)5855-5865
Number of pages11
JournalChemical Science
Issue number23
StatePublished - 21 Jun 2020


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