Inavolisib

Inavolisib is an inhibitor of PI3Kα (K_i = 0.034 nM).¹ It is selective for PI3Kα over PI3Kβ, PI3Kδ, and PI3Kγ (K_is = 99.7, 12.2, and 18.2 nM, respectively) and is 4.4-fold selective in decreasing the phosphorylated levels of proline-rich Akt substrate 40 kDa (PRAS40) in HCC1954 breast cancer cells, which express wild-type PI3K catalytic subunit p110α and p110α containing a histidine-to-arginine mutation at position 1047 (p110α^H1047R), over HDQ-P1 breast ductal carcinoma cells, which express only wild-type p110α. Inavolisib (111 nM) induces poly(ADP-ribose) polymerase (PARP) cleavage, a marker of apoptosis, in HCC1954 cells. It reduces the levels of phosphorylated Akt, PRAS40, and mutant p110α in HCC1954 cells, but not HDQ-P1 cells, when used at concentrations of 111, 333, and 1,000 nM. In vivo, inavolisib (25 or 50 mg/kg per day) decreases tumor volume in an HCC1954 mouse xenograft model.

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1. Hanan, E.J., Braun, M.G., Heald, R.A., et al. Discovery of GDC-0077 (inavolisib), a highly selective inhibitor and degrader of mutant PI3K. J. Med. Chem. 65(24), 16589-16621 (2022).