Casdatifan (AB521) is a novel and potent allosteric small molecule inhibitor of protumourigenic HIF-2α dependent transcription.

Background and purpose: Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor that mediates the expression of genes critical for cell adaptation and survival in low oxygen (hypoxic) conditions. In cancer, hypoxic conditions or molecular alterations within cancer cells can lead to HIF-2α accumulation and promote tumour growth and progression. Inactivating mutations in the von Hippel-Lindau (VHL) gene disable the oxygen-dependent HIF-2α degradation pathway and cause constitutive HIF-2α activity. VHL mutations are prevalent in clear cell renal cell carcinoma (ccRCC) where HIF-2α is a known tumourigenic driver. HIF-2α inhibition was shown to improve ccRCC patient outcomes clinically, warranting development of next-generation inhibitors.

Experimental approach: Pharmacological effects of a novel small molecule allosteric inhibitor of HIF-2α, AB521 (casdatifan), were evaluated using in vitro cell-based assays and in vivo mouse models.

Key results: AB521 inhibited HIF-2α-mediated transcription in cancer cells, endothelial cells, and M2-polarised macrophages. AB521 was selective for HIF-2α, displaying no activity against HIF-1α, and did not exhibit off-target cytotoxicity. When delivered orally to mice, AB521 caused dose-dependent decreases in HIF-2α-associated pharmacodynamic markers and significant regression of human ccRCC xenograft tumours. AB521 combined favourably with cabozantinib, a standard of care tyrosine kinase inhibitor, or zimberelimab, a clinical-stage anti-PD-1 antibody, in ccRCC xenograft studies.

Conclusions and implications: AB521 is a potent, selective and orally bioavailable HIF-2α inhibitor, with favourable pharmacological properties, that is being explored clinically for the treatment of ccRCC.