STX-478, a Mutant-Selective, Allosteric PI3Ka Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Ka-Mutant Xenografts.

Phosphoinositide 3-kinase a (PI3Ka) is one of the most mutated genes across cancers, especially breast, gynecological, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Ka inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Ka is associated with severe hyperglycemia and rash that limits alpelisib use and suggests that selectively targeting mutant PI3Ka could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Ka inhibitor that selectively targets prevalent PI3Ka helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.