2. Academic Validation
  3. Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC)

Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC)

  • J Med Chem. 2021 Jan 28;64(2):909-924. doi: 10.1021/acs.jmedchem.0c01563.
Zhuming Zhang 1,  Peter J Connolly 1,  Heng Keang Lim 1,  Vineet Pande 2,  Lieven Meerpoel 2,  Christopher Teleha 1,  Jonathan R Branch 1,  Janine Ondrus 1,  Ian Hickson 1,  Tammy Bush 1,  Leopoldo Luistro 1,  Kathryn Packman 3,  James R Bischoff 1,  Salam Ibrahim 1,  Christopher Parrett 4,  Yolanda Chong 2,  Marco M Gottardis 1,  Gilles Bignan 1
Affiliations

Affiliations

  • 1 Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
  • 2 Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 3 Janssen Research and Development, Cambridge, Massachusetts 02142, United States.
  • 4 VWR Avantor, Spring House, Pennsylvania 19477, United States.
PMID: 33470111 DOI: 10.1021/acs.jmedchem.0c01563
Abstract

Persistent Androgen Receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate Cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate Cancer (CRPC).

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