Preclinical evaluation of LX-086, a small molecule as a selective inhibitor of PI3K.

e15662 Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. PI3Kα is ubiquitously expressed, and associates with angiogenesis and glucose homeostasis. Gain of function mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common somatic alterations in solid tumors. The purpose of this study is to investigate the in vitro/ in vivo antitumor activity, and safety of LX-086, a small molecule of PI3Kα selective inhibitor, in preclinical models of solid cancer with PIK3CA mutation or amplification. Methods: Kinase inhibitory activity and selectivity of LX-086 were determined with PI3K kinase assays. Cellular pAkt S473 inhibitory activity and selectivity were evaluated in BT-474, MDA-MB-468, RAW264.7 and Jeko-1 cell lines (cell lines PI3Kα/β/γ/δ are specifically highly expressed respectively). The antitumor activity of LX-086 was evaluated in vivo in PIK3CA amplified or mutant breast cancer BT-474, T47D and ovarian cancer SK-OV-3 cell-derived mouse xenograft (CDX) models. Results: LX-086 displayed potent kinase inhibitory activity for WT PI3Kα, PI3Kα E545K , PI3Kα H1047R with IC 50 1.80 nM/1.13 nM/0.69 nM, respectively. LX-086 inhibited cell pAkt S473 in BT-474 cells with IC 50 35.4 nM. The selectivity of LX-086 in PI3Kα over PI3Kβ/δ/γ is similar with that of alpelisib, which had been approved by FDA in 2019. LX-086 showed antitumor efficacy in HER2+/HR+, PIK3CA amplified breast cancer BT-474 CDX model (TGI = 106% @40 mpk, QD), as well as in the HER2-/HR+, PIK3CA H1047R breast cancer T47D CDX model ( TGI = 84.7%@ 40 mpk, QD) and PIK3CA H1047R ovarian cancer SK-OV-3 CDX model ( TGI = 69.2%@ 40 mpk, QD). The 28-days toxicity study in dog also indicated that LX-086 had similar therapeutic index with alpelisib, with low risk of hyperglycemia. Conclusions: We have identified a novel potent and safe PI3Kα inhibitor LX-086. Preclinical studies show antitumor efficacy of LX-086 in PIK3CA mutant and amplified solid cancer models. LX-086 represents a promising clinical candidate for the treatment of solid cancers with PIK3CA mutation or amplification.