Development of a Scalable Synthesis of Casdatifan (AB521), a Potent, Selective, Clinical-Stage Inhibitor of HIF-2α

Casdatifan (AB521) is a potent and selective inhibitor of HIF-2α, currently under clinical evaluation for the treatment of clear cell renal cell carcinoma (ccRCC). Here, we report the development of a scalable synthesis of casdatifan, which was used to support its preclinical characterization and the initiation of phase 1 clinical studies. A convergent approach to assembling the tetracyclic scaffold and the development of efficient routes to key intermediates enabled the successful delivery of material to meet clinical development timelines. Crucial to the efficiency of the synthesis was the strategic design of synthetic routes that leverage a combination of substrate and catalyst control to set each of the 5 stereocenters found in the molecule with exquisite selectivity.