PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

被引：633

作者：

Raina, Kanak ^{[1
]}

Lu, Jing ^{[1
]}

Qian, Yimin ^{[1
]}

Altieri, Martha ^{[1
]}

Gordon, Deborah ^{[1
]}

Rossi, Ann Marie K. ^{[1
]}

Wang, Jing ^{[1
]}

Chen, Xin ^{[1
]}

Dong, Hanqing ^{[1
]}

Siu, Kam ^{[1
]}

Winkler, James D. ^{[1
]}

Crew, Andrew P. ^{[1
]}

Crews, Craig M. ^{[2
,3
,4
]}

Coleman, Kevin G. ^{[1
]}

机构：

[1] Arvinas LLC, New Haven, CT 06511 USA

[2] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA

[3] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA

[4] Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 26期

关键词：

BET; BRD4; protein degradation; prostate; PROTAC; RECEPTOR SPLICE VARIANTS; LENGTH ANDROGEN RECEPTOR; SMALL-MOLECULE PROTACS; BROMODOMAIN PROTEINS; INCREASED SURVIVAL; BREAST-CANCER; ENZALUTAMIDE; DEPRIVATION; ABIRATERONE; INHIBITION;

D O I：

10.1073/pnas.1521738113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extraterminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

引用

页码：7124 / 7129

页数：6

共 42 条

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