2. Academic Validation
  3. Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors

Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors

  • ACS Med Chem Lett. 2024 Feb 7;15(3):381-387. doi: 10.1021/acsmedchemlett.3c00543.
Lindsey G DeRatt 1,  E Christine Pietsch 1,  Justin S Cisar 1,  Edgar Jacoby 2,  Faraz Kazmi 1,  Rosalie Matico 1,  Paul Shaffer 1,  Alexandra Tanner 1,  Weixue Wang 1,  Ricardo Attar 1,  James P Edwards 1,  Scott D Kuduk 1
Affiliations

Affiliations

  • 1 Janssen Pharmaceutical Research and Development, 1400 McKean Rd., Spring House, Pennsylvania 19477, United States.
  • 2 Janssen Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
PMID: 38505861 DOI: 10.1021/acsmedchemlett.3c00543
Abstract

Dihydroorotate Dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required.

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