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.

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Publication Details

Journal
Organic Process Research & Development
Published
2025-02-05
DOI
https://doi.org/10.1021/acs.oprd.4c00497
Citations
2
Primary Topic
Asymmetric Hydrogenation and Catalysis
Type
article
Field-Weighted Citation Impact
1.07
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article

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

Balint Gal, Karl T. Haelsig, Samuel L. Drew, Jarosław Kalisiak et al.
2 citations
Organic Process Research & Development
Asymmetric Hydrogenation and Catalysis
1.07
article

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

Balint Gal, Karl T. Haelsig, Samuel L. Drew, Jarosław Kalisiak, Guillaume Mata, Anh Tran, Jeremy Fournier, Manmohan R. Leleti, Brandon R. Rosen, Joel W. Beatty, Jay P. Powers, Kenneth V. Lawson, Clayton Hardman, Artur K. Mailyan, Zhang Wang, Kai Yu, Matthew Epplin
article en
2 citations

Abstract

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.

Organic Process Research & DevelopmentVol. 29(2)
Profectus Biosciences (United States) (US), Arcadia Biosciences (United States) (US)
Openalex Percentile: Top 26%
Asymmetric Hydrogenation and Catalysis
1.07
DOISourceOpenAlex
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Development of a Scalable Synthesis of Casdatifan (AB521), a Potent, Selective, Clinical-Stage Inhibitor of HIF-2α — Balint Gal, Karl T. Haelsig, et al. · Organic Process Research & Development (2025) | TGRS Research Map | TGRS