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
  • 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.