Abstract A002: Targeting hypoxia inducible factor (HIF)-2α with AB521, a novel and potent small molecule HIF-2α inhibitor, for the treatment of clear cell renal cell carcinoma
Authors: Piovesan Dana , Cho Soonweng , Lawson Kenneth V. , Liao Kai H. , Foster Paul G. , Cheng Tzuling , Walters Matthew J. , Gauthier Kelsey E. Sivick 
Published: August 2023

Abstract
Cells in the solid tumor microenvironment are frequently exposed to hypoxic or pseudohypoxic conditions, necessitating molecular adaptations such as induction of transcriptional programs for survival. HIF-2α is a transcriptional regulator of hypoxia-induced genes that is regulated post-translationally in an oxygen-dependent manner via hydroxylation by prolyl hydroxylase enzymes - a modification required for recognition by pVHL for subsequent degradation. Therefore, under hypoxic conditions or in the case of pVHL inactivation (pseudohypoxia), HIF-2α is stabilized and translocates to the nucleus where it forms a heterodimer with ARNT to initiate transcription of its target genes. HIF-2α has been shown to be an oncogenic driver in clear cell renal cell carcinoma (ccRCC) where VHL mutations occur frequently, resulting in a pseudohypoxic state and stable HIF-2α expression. There is both preclinical and clinical evidence in ccRCC demonstrating that inhibiting HIF-2α is a valid therapeutic approach in blocking tumor progression. AB521 is a clinical-stage novel and potent small-molecule HIF-2α inhibitor. In vitro, AB521 effectively inhibits transcription of pro-tumorigenic HIF-2α target genes in multiple human cell types relevant to the tumor microenvironment, including cancer cells, primary endothelial cells, and pro-tumorigenic M2-polarized macrophages. AB521 also blocks HIF-2α-mediated gene transcription in vivo, as detected using both intratumoral and peripheral markers, an activity that is accompanied by a marked reduction in tumor burden in two VHL-mutant ccRCC xenograft models. Supporting a potential combinatorial treatment approach for HIF-2α inhibition in ccRCC, AB521 combines favorably with standard-of-care tyrosine kinase inhibitor cabozantinib in mouse models, further enhancing tumor efficacy in VHL-mutant ccRCC compared to either single agent alone. In healthy human volunteers, AB521 exhibits favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties including a half-life of 18-24 hours, supportive of once-daily dosing, dose-dependent reductions in serum erythropoietin (EPO) following a single dose of 10 to 100 mg, and sustained EPO reduction after multiple daily dosing. In summary, AB521 is a potent and selective HIF-2α inhibitor that has been thoroughly characterized in a suite of in vitro assays, reduces tumor burden in ccRCC xenografts both as a single agent and in combination with cabozantinib, and exhibits favorable PK/PD properties in human healthy volunteers. Phase I clinical evaluation of AB521 in subjects with ccRCC and other solid tumors has been initiated and is currently ongoing (NCT05536141).
Citation Format: Dana Piovesan, Soonweng Cho, Kenneth V. Lawson, Kai H. Liao, Paul G. Foster, Tzuling Cheng, Matthew J. Walters, Kelsey E. Sivick Gauthier. Targeting hypoxia inducible factor (HIF)-2α with AB521, a novel and potent small molecule HIF-2α inhibitor, for the treatment of clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A002.