2. Academic Validation
  3. Discovery of Casdatifan, Part I: Design and Characterization of Tetrahydroquinoline Inhibitors of Hypoxia-Inducible Factor-2α

Discovery of Casdatifan, Part I: Design and Characterization of Tetrahydroquinoline Inhibitors of Hypoxia-Inducible Factor-2α

  • J Med Chem. 2026 Jun 25;69(12):14921-14951. doi: 10.1021/acs.jmedchem.5c03647.
Guillaume Mata 1,  Artur K Mailyan 1,  Samuel L Drew 1,  Joel W Beatty 1,  Jeremy Fournier 1,  Brandon R Rosen 1,  Xuelei Yan 1,  Balint Gal 1,  Anh Tran 1,  Jaroslaw Kalisiak 1,  Jenna L Jeffrey 1,  Patricia Fabila 1,  Jennifer Au 1,  Cesar Meleza 1,  Ada Chen 1,  Pei-Yu Chen 1,  Casey Mitchell 1,  Kelsey E Sivick 1,  Lixia Jin 1,  Stephen W Young 1,  Matthew J Walters 1,  Nigel P Walker 1,  Manmohan R Leleti 1,  Jay P Powers 1,  Kenneth V Lawson 1
Affiliations

Affiliation

  • 1 Arcus Biosciences, Inc, Hayward, California 94545, United States.
PMID: 42053090 DOI: 10.1021/acs.jmedchem.5c03647
Abstract

Disruption of hypoxia-inducible factor (HIF) signaling is implicated in multiple diseases, including clear cell renal cell carcinoma (ccRCC), where HIF-2α functions as a key oncogenic driver. Here, we report the design and structure-activity relationships of a novel class of N-aryl-substituted tetrahydroquinolines that bind the HIF-2α PAS-B domain with high affinity. Structural and biophysical studies revealed that ligand binding induces localized conformational perturbations at the dimerization interface between HIF-2α and HIF-1β. Notably, incorporation of cis-vicinal difluorination was critical for productive engagement of the lipophilic pocket, with hyperconjugative effects contributing to improved binding efficiency and facial polarization enhancing physicochemical properties. These features translated into improved biochemical and cellular activity, including inhibition of hypoxia-regulated gene expression. Insights from this campaign ultimately informed the discovery of casdatifan, a clinical-stage HIF-2α inhibitor, underscoring the translational potential of this novel chemotype.

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