Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML
Lindsey G. DeRatt, Zhuming Zhang, Christine Pietsch, Justin S. Cisar, Xiaochun Zhang, Weixue Wang, Alexandra Tanner, Rosalie Matico, P.L. Shaffer, Edgar Jacoby, Faraz Kazmi, Neetu Shukla, Tammy L. Bush, Aaron Patrick, Ulrike Philippar, Ricardo M. Attar, James P. Edwards, Scott D. Kuduk
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).