PI3K inhibitors: review and new strategies

The search is on for effective specific inhibitors for PI3K alpha mutants. PI3K alpha, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110 alpha catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3K alpha 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 PI3K alpha isoform-specific, is undergoing clinical trials. Not surprisingly, these ATP-competitive drugs commonly elicit severe concentration-dependent side effects. Here we briefly review PI3K alpha mutations, focus on PI3K drug repertoire and propose new, to-date unexplored PI3K alpha therapeutic strategies. These include (1) an allosteric and orthosteric inhibitor combination and (2) taking advantage of allosteric rescue mutations to guide drug discovery.