预约演示
更新于：2026-04-04
CC-94676
更新于：2026-04-04
概要
基本信息
药物类型 小分子化药、蛋白水解靶向嵌合体（PROTAC） |
别名 AR-LDD、BMS-986365、CC 94676 |
靶点 |
作用方式 降解剂 |
作用机制 AR 降解剂(雄激素受体 降解剂) |
在研适应症 |
非在研适应症- |
原研机构 |
非在研机构- |
权益机构- |
最高研发阶段临床3期 |
首次获批日期- |
最高研发阶段(中国)临床3期 |
特殊审评- |
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结构/序列
分子式C41H45F3N8O5S |
InChIKeyYUVGVJYLOFTILT-NHYGQJMQSA-N |
CAS号2446928-30-7 |
关联
5
项与 CC-94676 相关的临床试验NCT07242781
A Phase 1, Open-label, 2-part, Fixed-sequence, Crossover Study to Evaluate the Effect of Cytochrome P450 (CYP) 3A Inhibitor (Itraconazole) and Inducer (Rifampin) on the Pharmacokinetics of AR-LDD (BMS-986365) in Healthy Adult Male Participants
NCT06764485
A Phase 3, Two-part, Randomized, Open-label, Adaptive Study Comparing BMS-986365 Versus Investigator's Choice of Therapy Comprising Either Docetaxel or Second Androgen Receptor Pathway Inhibitor (ARPI), in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) - rechARge
NCT06433505
A Phase 1, Open-label, Two-Part Study to Evaluate the Pharmacokinetics, Metabolism and Excretion, and Absolute Bioavailability of BMS-986365 in Healthy Male Participants
100 项与 CC-94676 相关的临床结果
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100 项与 CC-94676 相关的转化医学
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100 项与 CC-94676 相关的专利（医药）
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4
项与 CC-94676 相关的文献（医药）2026-01-06CLINICAL CANCER RESEARCH
Discovery of BMS-986365, a First-in-Class Dual Androgen Receptor Ligand-Directed Degrader and Antagonist, for the Treatment of Advanced Prostate Cancer
Article
作者: Mortensen, Deborah S. ; Xu, Shuichan ; Wardell, Suzanne E. ; Liao, Debbie ; Rolfe, Mark ; McDonnell, Donald P. ; Cathers, Brian ; Hamann, Lawrence G. ; Ammirante, Massimo ; Toyama, Brandon ; Piccotti, Joseph R. ; Rathkopf, Dana ; Pierce, Daniel W. ; Arora, Vivek K. ; Rychak, Emily ; Reiss, Samantha ; Khater, Marwa ; Baughman, Joshua M. ; Christoforou, Andy ; Tran, Minerva ; Bence, Neil ; Norris, John D. ; Plantevin-Krenitsky, Veronique ; Liu, Ken ; Meiring, Joseph ; Nayak, Surendra ; Narla, Rama Krishna ; Fontanillo, Celia ; Tsuji, Toshiya ; Hansen, Joshua D. ; Kandimalla, Raju
Abstract:
Purpose::
BMS-986365, a heterobifunctional androgen receptor (AR) ligand-directed degrader, was designed as a potent cereblon-dependent degrader and competitive antagonist of the AR to overcome resistance to AR pathway inhibition (ARPI) in metastatic prostate cancer.
Experimental Design::
The in vitro impact of BMS-986365–induced AR degradation on AR activity and prostate cancer cell proliferation was evaluated. Intrinsic agonistic and antagonist activities of BMS-986365 were assessed. The in vivo antitumor activity of BMS-986365 was compared with enzalutamide in multiple cell line– or patient-derived prostate cancer models.
Results::
BMS-986365 is a potent, rapid, and selective degrader of AR wild-type (WT) and most of the clinically relevant mutants. Degradation of both WT and mutant AR is the key driver of BMS-986365 efficacy, with additional antagonism of residual AR activity enabled through occupancy of its ligand-binding domain. Compared with enzalutamide, BMS-986365 more efficiently inhibits AR target gene transcription and AR-dependent proliferation of prostate cancer cell lines. Whereas enzalutamide increased AR protein in metastatic castration-resistant prostate cancer (CRPC) models, BMS-986365 maintained low levels of AR protein despite increased AR transcript levels. In vivo, BMS-986365 demonstrated on-target activity, degrading AR, suppressing AR signaling, and inhibiting growth in validated cell line– and patient-derived xenograft models of castration-sensitive prostate cancer and advanced and/or therapy-resistant CRPC. Clinically, BMS-986365 reduced PSA in patients with metastatic CRPC after ARPI, including patients with WT AR.
Conclusions::
The preclinical observations, coupled with clinical data, strongly support the potential for BMS-986365 to overcome ARPI-resistant disease regardless of AR mutational status. These findings establish BMS-986365 as a first-in-class dual AR degrader and competitive antagonist, likely to emerge as an important tool in the armamentarium to treat prostate cancer.See related commentary by Nyquist and Nelson, p. 13
2025-06-09Future Oncology
rechARge: a randomized phase III trial of the androgen receptor ligand-directed degrader, BMS-986365, vs investigator’s choice in patients with mCRPC
Article
作者: Barthélémy, Philippe ; Matsubara, Nobuaki ; Thiery-Vuillemin, Antoine ; Rathkopf, Dana E ; Kreiser, Stephanie ; McKay, Rana R ; Cascella, Teresa ; Irincheeva, Irina ; Sandhu, Shahneen ; Arranz, Jose A ; Hadaschik, Boris ; Shore, Neal D ; Ye, Dingwei ; Chi, Kim Nguyen
There is an ongoing need for efficacious, life-prolonging therapies for males with metastatic castration-resistant prostate cancer (mCRPC). mCRPC that progresses after treatment with androgen receptor pathway inhibitors (ARPIs) may still be driven by AR signaling. BMS-986365 is a heterobifunctional, orally bioavailable ligand-directed degrader that targets the AR through a first-in-class dual mechanism of AR degradation and antagonism. Here, we present the study design of rechARge, a phase III, randomized, multicenter, adaptive, two-part, open-label trial evaluating BMS-986365 versus investigator's choice of therapy comprising either docetaxel or a switch to an alternative ARPI (abiraterone or enzalutamide) in patients with mCRPC whose disease has progressed after treatment with one prior ARPI. The primary study objective is to compare the efficacy and safety of BMS-986365 versus investigator's choice of therapy. Approximately 960 patients will be enrolled.Clinical trial registration: www.clinicaltrials.gov identifier is NCT06764485.
2025-05-08JOURNAL OF MEDICINAL CHEMISTRY
In Vitro ADME Profiling of PROTACs: Successes, Challenges, and Lessons Learned from Analysis of Clinical PROTACs from a Diverse Physicochemical Space
Article
作者: Nash, Samuel ; Pike, Andy ; Swedrowska, Magda ; Srivastava, Abhishek ; Grime, Ken
Established in vitro assays for ADME properties often struggle with compounds outside of the rule-of-5 space such as PROTACs. These bifunctional molecules, due to high lipophilicity and molecular weight, frequently exhibit low solubility, high nonspecific binding, and poor translation of assay data, necessitating empirical validation. This study evaluates the performance of standard ADME screening assays exemplified by 10 PROTACs in clinical development, with varying lipophilicity, in the context of the AstraZeneca data set. Assessment of in vitro metabolic clearance, plasma protein and incubation binding, blood-to-plasma ratio, Caco-2 permeability, and efflux was performed. Additionally, due to the poor performance of the aqueous solubility assay, the impact of biorelevant media was investigated on solubility. The primary objective was to evaluate the suitability of traditional ADME assays for PROTACs and understand the lipophilicity limits. This work aims to guide discovery teams on assay reliability and performance and inform decision-making regarding compound progression in this challenging area.
41
项与 CC-94676 相关的新闻（医药）2026-03-31
蛋白降解靶向嵌合体
100 项与 CC-94676 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 转移性去势抵抗性前列腺癌 | 临床3期 | 美国 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 中国 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 日本 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 阿根廷 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 澳大利亚 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 奥地利 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 巴西 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 加拿大 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 智利 | 2025-03-13 | |
| 转移性去势抵抗性前列腺癌 | 临床3期 | 捷克 | 2025-03-13 |
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临床结果
临床结果
适应症
分期
评价
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临床1期 | 60 | 網繭繭鑰繭鏇獵壓遞繭(蓋醖鹽壓鑰鹹憲蓋壓壓) = The most common TRAE were prolonged QTc (asymptomatic) (47%; G3 10%), bradycardia (37%; G3 0%), and fatigue (22%; G3 0%). G3 QTc prolongation was successfully managed by dose reduction. 選獵憲製鬱構網製範願 (衊鏇淵簾夢鹽窪鏇窪網 ) | 积极 | 2024-09-16 | |||
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