title: Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer.
abstract: 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.
authors: Bristol-Myers Squibb Company, Princeton, New Jersey, USA. rattar1@its.jnj.com
authors: Ricardo M
authors: RM
authors: Attar
authors: Maria
authors: M
authors: Jure-Kunkel
authors: Aaron
authors: A
authors: Balog
authors: Mary Ellen
authors: ME
authors: Cvijic
authors: Janet
authors: J
authors: Dell-John
authors: Cheryl A
authors: CA
authors: Rizzo
authors: Liang
authors: L
authors: Schweizer
authors: Thomas E
authors: TE
authors: Spires
authors: J Suso
authors: JS
authors: Platero
authors: Mary
authors: M
authors: Obermeier
authors: Weifang
authors: W
authors: Shan
authors: Mark E
authors: ME
authors: Salvati
authors: William R
authors: WR
authors: Foster
authors: Joseph
authors: J
authors: Dinchuk
authors: Shen-Jue
authors: SJ
authors: Chen
authors: Gregory
authors: G
authors: Vite
authors: Robert
authors: R
authors: Kramer
authors: Marco M
authors: MM
authors: Gottardis
mesh_terms: 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
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; C543412:BMS 641988; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007094:Imides