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Ref Type abstract
PMID
Authors Molly A Taylor; Qian Zhao; David Mareska; Maria Hoh; Yevgeniy Izrayelit; Kevin Litwiler; Mark L Boys; Rich Woessner; Duncan Walker; Jennifer Diamond; James D Winkler
Title Abstract B163: Discovery and characterization of OKI-219, an orally bioavailable H1047R-mutant-selective inhibitor of PI3Ka
Journal Vol Issue Date Pages Journal Short Title
Molecular Cancer Therapeutics 22 12_Supplement December 1, 2023
URL https://aacrjournals.org/mct/article/22/12_Supplement/B163/730741
Abstract Text Mutations in PI3Kα lead to constitutive activation of the PI3K/AKT/mTOR pathway and are found in approximately 13% of human cancers, with the PI3KαH1047R mutation being the most common. Targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies. However, treatment with non-mutant selective PI3Kα inhibitors, such as alpelisib, is associated with significant toxicities such as hyperglycemia due to on-target inhibition of the wild-type enzyme, which often leads to dose modification or discontinuation. Therefore, there is a significant need to develop new PI3Kα-targeted therapies that can avoid or minimize on-target toxicity and improve the safety and clinical benefit for patients.  OKI-219 is a PI3KαH1047R mutant-selective inhibitor, with ~100-fold cellular selectivity for the H1047R mutation over wild-type and biochemical selectivity across a 412 kinase panel, with no other kinases showing >30% inhibition at 1 µM. In vitro, OKI-219 drives decreased phosphorylated AKT (pAKT) and decreased proliferation selectively in PI3KαH1047R mutant cell lines across several tumor types. In vivo, as a monotherapy, OKI-219 demonstrates dose-dependent antitumor activity in multiple human CDX and PDX tumor xenograft models, with regression rates up to 100% in PI3KαH1047R heterozygous (T47D) and homozygous (SUM185PE) CDX models, at doses that show no sign of the metabolic dysfunction (increased glucose or insulin) that is associated with wild-type protein inhibition. The in vivo antitumor activity correlates with pathway inhibition, measured by decreased pAKT in tumors. In addition to the monotherapy efficacy observed, OKI-219 in combination with the selective estrogen receptor degrader (SERD) fulvestrant showed significant combination benefit leading to tumor regressions in the H1047R-mutated ER+HER2- breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. These data support the hypothesis that OKI-219 will offer improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. This hypothesis will be tested, as OKI-219 is moving into clinical investigation.

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