21: AB521 is a Novel and Potent Clinical-stage HIF-2α Inhibitor for the Treatment of Renal Cell Carcinoma
Location: Poster Hall, Board D4
Cesar Meleza, BS; Suan Liu, BS ; Ferdie Soriano, BS ; Elaine Ginn, BS ; Lisa Seitz, MA ; Dana Piovesan, MSc; Matthew Walters, PhD; Paul Foster, PhD; Manmohan Leleti, PhD; Patrick Schweickert, PhD ; Jeremy Fournier, PhD ; Kenneth Lawson, PhD ; Soonweng Cho , PhD B11; Artur Mailyan, PhD; Guillaume Mata , PhD; Kai Yu, PhD ; Lixia Jin, PhD ; Elaine Peterson, PhD ; Ken Liao, PhD
Director, Biology Arcus Biosciences Hayward, California, United States
Background. The transcription factor Hypoxia-inducible Factor (HIF)-2α is an oncogenic driver in clear cell renal cell carcinoma (ccRCC). HIF-2α protein levels are regulated post-translationally in an oxygen-dependent manner. Hypoxic or pseudohypoxic conditions promote HIF-2α stabilization and transcription of pro-tumorigenic genes. Inhibition of HIF-2α has significant potential to mitigate tumor growth, particularly in cancers like ccRCC that have a high prevalence of molecular alterations associated with pseudohypoxia, namely epigenetic or mutational silencing of the Von Hippel-Lindau protein. Herein we report findings associated with bioinformatic gene signature analyses and characterize AB521, a novel small molecule HIF-2α inhibitor.
Methods. Published and novel gene signatures were applied to publicly available datasets. Potency and specificity of AB521 was evaluated using biochemical and cell-based assays. Efficacy, pharmacokinetics, and pharmacodynamics associated with AB521 were evaluated in preclinical species.
Results. Evaluated signatures related to hypoxia and HIF-2α were associated with therapeutic response to HIF-2α inhibition in preclinical models. Binding assays and crystal structure elucidation demonstrated that AB521 avidly binds the HIF-2α PAS-B domain. AB521 potently inhibited HIF-2α-dependent reporter transcription and VEGF protein secretion in 786-O cells. AB521 also selectively inhibited HIF-2α-, but not HIF-1α-, regulated gene expression in Hep3B hepatocellular carcinoma cells. In vivo, AB521 significantly regressed mouse ccRCC xenograft tumors and decreased on-target pharmacodynamic markers in a dose-dependent manner. Additionally, AB521 enhanced anti-tumor activity of a VEGF-targeting tyrosine kinase inhibitor. Finally, AB521 had a favorable pharmacokinetics in vitro and in vivo, resulting in a pharmacokinetic profile suitable for once-daily oral dosing in humans.
Conclusions. Transcriptional data can be further applied to understand the therapeutic potential of HIF-2α inhibition. AB521 is a novel and selective HIF-2α inhibitor with profound anti-tumor activity, and clinical evaluation of this molecule is underway.