Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer

被引：12

作者：

Chen, Zhixiang ^{[1
,2
,3
]}

Wang, Mi ^{[1
,2
,3
]}

Wu, Dimin ^{[1
,2
,3
]}

Zhao, Lijie ^{[1
,2
,3
]}

Metwally, Hoda ^{[1
,2
,3
]}

Jiang, Wei ^{[1
,2
,3
]}

Wang, Yu ^{[1
,2
,3
]}

Bai, Longchuan ^{[1
,2
,3
]}

Mceachern, Donna ^{[1
,2
,3
]}

Luo, Jie ^{[4
]}

Wang, Meilin ^{[5
]}

Li, Qiuxia ^{[5
]}

Matvekas, Aleksas ^{[5
]}

Wen, Bo ^{[5
]}

Sun, Duxin ^{[5
]}

Chinnaiyan, Arul M. ^{[4
]}

Wang, Shaomeng ^{[1
,2
,3
]}

机构：

[1] Univ Michigan, Rogel Canc Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Michigan Ctr Translat Pathol, Rogel Canc Ctr, Med Sch, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 07期

关键词：

ANDROGEN RECEPTOR; BROMODOMAIN INHIBITOR; CBP; ABIRATERONE; RESISTANCE; PROTEIN; P300;

D O I：

10.1021/acs.jmedchem.3c01789

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.

引用

页码：5351 / 5372

页数：22

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