N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia

  • J Med Chem. 2022 Aug 25;65(16):11241-11256. doi: 10.1021/acs.jmedchem.2c00788.
Justin S Cisar  1 ,  Christine Pietsch  1 ,  Lindsey G DeRatt  1 ,  Edgar Jacoby  2 ,  Faraz Kazmi  1 ,  Colleen Keohane  1 ,  Katie Legenski  1 ,  Rosalie Matico  1 ,  Paul Shaffer  1 ,  Yvan Simonnet  1 ,  Alexandra Tanner  1 ,  Chao-Yuan Wang  1 ,  Weixue Wang  1 ,  Ricardo Attar  1 ,  James P Edwards  3 ,  Scott D Kuduk  1
Affiliations
  • 1. Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States.
  • 2. Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 3. Janssen Research and Development, San Diego, California 92121, United States.
PMID: 35925768 DOI: 10.1021/acs.jmedchem.2c00788
Abstract

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate Dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.

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