Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically Relevant Ligand Binding Domain Mutations in Metastatic Castration-Resistant Prostate Cancer.

Autor:	Branch JR; Janssen Research and Development, Spring House, Pennsylvania. jbranch@its.jnj.com gbignan@its.jnj.com., Bush TL; Janssen Research and Development, Spring House, Pennsylvania., Pande V; Janssen Research and Development, Beerse, Belgium., Connolly PJ; Janssen Research and Development, Spring House, Pennsylvania., Zhang Z; Janssen Research and Development, Spring House, Pennsylvania., Hickson I; Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, United Kingdom., Ondrus J; Janssen Research and Development, Spring House, Pennsylvania., Jaensch S; Janssen Research and Development, Beerse, Belgium., Bischoff JR; F. Hoffmann-La Roche Ltd, Molecular Targeted Therapies (Oncology), Basel, Switzerland., Habineza G; Merck, North Wales, Pennsylvania., Van Hecke G; Janssen Research and Development, Beerse, Belgium., Meerpoel L; Janssen Research and Development, Beerse, Belgium., Packman K; Janssen Research and Development, Boston, Massachusetts., Parrett CJ; VWR Avantor, Spring House, Pennsylvania., Chong YT; Recursion Pharmaceuticals, Salt Lake City, Utah., Gottardis MM; Janssen Research and Development, Spring House, Pennsylvania., Bignan G; Janssen Research and Development, Raritan, New Jersey. jbranch@its.jnj.com gbignan@its.jnj.com.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 May; Vol. 20 (5), pp. 763-774. Date of Electronic Publication: 2021 Mar 01.
DOI:	10.1158/1535-7163.MCT-20-0510
Abstrakt:	Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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