Tersolisib

Tersolisib is an allosteric inhibitor of kinase-domain mutant forms of PI3Kα.¹ It inhibits PI3Kα containing mutations at the histidine in position 1047, including PI3Kα^H1047R, the methionine in position 1043, including PI3Kα^M1043I, and the glycine in position 1049, including PI3Kα^G1049R. It is selective for PI3Kα containing the kinase-domain mutation H1047R (PI3Kα^H1047R) over wild-type PI3Kα and PI3Kα containing the helical-domain mutations E542K (PI3Kα^E542K) or E545K (PI3Kα^E545K; IC₅₀s = 9.4, 131, 113, and 71 nM, respectively). It is also selective for PI3Kα^H1047R over 372 kinases in a kinome screen, but does inhibit Aurora B kinase, at 10 µM. Tersolisib selectively inhibits the proliferation of a variety of cancer cell lines containing PI3Kα^H1047R (IC₅₀s = 15-211 nM) over SK-BR-3 cells containing wild-type PI3Kα (IC₅₀ = 319 nM). It reduces tumor growth in GP2d colon, NCI-H1048 small cell lung, Detroit 562 head and neck squamous cell, and HCC1954 hormone receptor-negative, HER2-positive (HR^-HER2⁺) breast cancer mouse xenograft models when administered at a dose of 100 mg/kg once per day.

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1. Buckbinder, L., St Jean, D.J., Jr., Tieu, T., et al. STX-478, a mutant-selective, allosteric PI3Kα inhibitor spares metabolic dysfunction and improves therapeutic response in PI3Kα-mutant xenografts. Cancer Discov. 13(11), 2432-2447 (2023).