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).

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