Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer.
Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the approximately 30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer.
Attar
Ricardo M
RM
Bristol-Myers Squibb Company, Princeton, New Jersey, USA. rattar1@its.jnj.com
Jure-Kunkel
Maria
M
Balog
Aaron
A
Cvijic
Mary Ellen
ME
Dell-John
Janet
J
Rizzo
Cheryl A
CA
Schweizer
Liang
L
Spires
Thomas E
TE
Platero
J Suso
JS
Obermeier
Mary
M
Shan
Weifang
W
Salvati
Mark E
ME
Foster
William R
WR
Dinchuk
Joseph
J
Chen
Shen-Jue
SJ
Vite
Gregory
G
Kramer
Robert
R
Gottardis
Marco M
MM
D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007094:Imides / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; C543412:BMS 641988; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007094:Imides