46P AB521, a clinical-stage, potent, and selective Hypoxia-Inducible Factor (HIF)-2α inhibitor, for the treatment of renal cell carcinoma

The transcription factor hypoxia-inducible 2α (HIF-2α) is a key oncogenic driver in clear cell renal carcinoma (ccRCC). HIF-2α protein levels are tightly regulated post-translationally an oxygen-dependent manner. Hypoxic conditions or aberrations the Von-Hippel Lindau (VHL) ubiquitin ligase complex lead to stabilization and of various pro-tumorigenic gene sets. Clinical evidence indicates that inhibition effective strategy mitigate tumor growth, particularly ccRCC, cancer has high prevalence pVHL dysfunction. Herein we present discovery characterization AB521, potent selective small molecule inhibitor exhibits profound antitumor activity preclinical models. potency AB521 was evaluated using suite biochemical cell-based assays. Efficacy pharmacodynamic markers were also mice bearing established A498 786-O ccRCC xenograft tumors treated with alone combination cabozantinib. Biochemical binding assays co-crystal structure elucidation demonstrated avidly binds PAS-B domain lipophilic cavity. potently inhibited HIF-2α-dependent reporter VEGF secretion cells. selectively HIF-2α-, but not HIF-1α-, expression Hep3B hepatocellular significantly regressed mouse decreased on-target dose-dependent Additionally, cabozantinib, showed enhanced anti-tumor model relative either single agent therapy. Finally, had favorable pharmacokinetics species, resulting projected pharmacokinetic profile suitable for once-daily dosing humans, which may result higher level other clinical candidates this space. novel activity, evaluation underway.