Discovery of Tetrasubstituted Quinazolin-4(3 <i>H</i> )-ones as Wild-type-sparing, Highly Selective PI3KαH1047R Inhibitors

Abstract Inhibiting PI3Kα has demonstrated promising therapeutic effects for patients with HR+/HER2− and PIK3CA-mutated advanced or metastatic breast cancer. However, hyperglycemia and other notable adverse events (AE) associated with concomitant wild-type inhibition remain a challenge and limit dosing. Selectively targeting the mutant PI3KαH1047R could reduce wild-type-driven AEs while retaining clinical efficacy. Herein, we report the design and identification of tetrasubstituted quinazolin-4(3H)-ones that can selectively inhibit PI3KαH1047R through a proposed slow-on and slow-off mechanism. Compound 34 demonstrated potent and mutant-selective in vitro activity and a good ADME profile. When dosed in a T47D mouse xenograft model, it displayed measurable and significant TGI (tumor growth inhibition) with no effect on either the serum insulin or blood glucose levels in contrast with the group dosed with an approved PI3Kα inhibitor. These promising findings demonstrate that a highly selective inhibitor of mutant PI3KαH1047R may address current on-target toxicity arising from PI3KαWT inhibitionthough further optimization of compound 34 to reduce the efficacious dose and address tolerability would be warranted.