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

Autor:	DeRatt LG; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Zhang Z; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Pietsch C; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Cisar JS; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Zhang X; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Wang W; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Tanner A; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Matico R; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Shaffer P; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Jacoby E; Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Kazmi F; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Shukla N; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Bush TL; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Patrick A; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Philippar U; Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Attar R; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Edwards JP; Janssen Research and Development, Spring House, Pennsylvania 19477, United States., Kuduk SD; Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 11254-11272. Date of Electronic Publication: 2024 Jun 18.
DOI:	10.1021/acs.jmedchem.4c00809
Abstrakt:	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).
Databáze:	MEDLINE
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