2. Academic Validation
  3. A carboxylic acid isostere screen of the DHODH inhibitor Brequinar

A carboxylic acid isostere screen of the DHODH inhibitor Brequinar

  • Bioorg Med Chem Lett. 2020 Nov 15;30(22):127589. doi: 10.1016/j.bmcl.2020.127589.
Lindsey G DeRatt 1,  E Christine Pietsch 2,  Alexandra Tanner 3,  Paul Shaffer 4,  Edgar Jacoby 5,  Weixue Wang 3,  Faraz Kazmi 6,  Xiaochun Zhang 2,  Ricardo M Attar 2,  James P Edwards 7,  Scott D Kuduk 8
Affiliations

Affiliations

  • 1 Discovery Chemistry, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA. Electronic address: [email protected].
  • 2 Oncology Discovery, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA.
  • 3 Discovery Technology and Molecular Pharmacology, Janssen Pharmaceutical Research & Development, Spring House, PA 19477, USA.
  • 4 Structural and Protein Sciences, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA.
  • 5 Discovery Chemistry, Janssen Pharmaceutical Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 6 Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA.
  • 7 Discovery Chemistry, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA.
  • 8 Discovery Chemistry, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA. Electronic address: [email protected].
PMID: 33007394 DOI: 10.1016/j.bmcl.2020.127589
Abstract

Dihydroorotate Dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.

Keywords

Acute myeloid leukemia; Brequinar; Dihydroorotate dehydrogenase; Inhibitor.

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