Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML

  • J Med Chem. 2024 Jul 11;67(13):11254-11272. doi: 10.1021/acs.jmedchem.4c00809.
Lindsey G DeRatt  1 ,  Zhuming Zhang  1 ,  Christine Pietsch  1 ,  Justin S Cisar  1 ,  Xiaochun Zhang  1 ,  Weixue Wang  1 ,  Alexandra Tanner  1 ,  Rosalie Matico  1 ,  Paul Shaffer  1 ,  Edgar Jacoby  2 ,  Faraz Kazmi  1 ,  Neetu Shukla  1 ,  Tammy L Bush  1 ,  Aaron Patrick  1 ,  Ulrike Philippar  2 ,  Ricardo Attar  1 ,  James P Edwards  1 ,  Scott D Kuduk  1
Affiliations
  • 1. Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
  • 2. Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
PMID: 38889244 DOI: 10.1021/acs.jmedchem.4c00809
Abstract

Acute myelogenous leukemia (AML), a heterogeneous 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 and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).