STX-478 (STX478) is a potent, mutant-selective, allosteric PI3Kα inhibitor with IC50 of 9.4 nM (PI3Kα H1047R), 14-fold selectivity over WT PI3Kα (IC50=131 nM).
STX-478 is less potent against E542K (IC50=113 nM) and E545K (IC50=71 nM) helical domain mutants, but not alpelisib (Cat# PC-20590).
STX-478 also demonstrates exquisite kinome-wide selectivity against a panel 373 kinases representing approximately 70% of the human kinome at 10 uM, including PI3Kβ, PI3Kδ, and PI3Kγ isoforms, with only one exception of AurB kinase (IC50=1.6 µM).
STX-478 selectively inhibits the proliferation of cell lines with kinase-domain and helical-domain mutations compared with cells expressing WT PI3Kα.
STX-478 selectively targets PI3Kα activity and cell viability in PI3Kα mutant cells.
STX-478 (100 mg/kg QD) exhibits robust anti-tumor efficacy in PI3Kα-mutant tumors without metabolic dysregulation in mice.
STX-478 is efficacious across a panel of PI3Kα-mutant CDX and PDX 17 tumors, without evidence of insulin resistance.