Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

被引：105

作者：

Andrews, Forest H. ^{[1
]}

Singh, Alok R. ^{[2
,3
]}

Joshi, Shweta ^{[2
,3
]}

Smith, Cassandra A. ^{[4
]}

Morales, Guillermo A. ^{[1
,5
]}

Garlich, Joseph R. ^{[5
]}

Durden, Donald L. ^{[2
,3
,5
]}

Kutateladze, Tatiana G. ^{[1
,4
]}

机构：

[1] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA

[2] UC San Diego Sch Med, Dept Pediat, Moores Canc Ctr, Div Pediat Hematol Oncol, La Jolla, CA 92130 USA

[3] Rady Childrens Hosp San Diego, San Diego, CA 92123 USA

[4] Univ Colorado, Program Struct Biol & Biochem, Sch Med, Aurora, CO 80045 USA

[5] SignalRx Pharmaceut Inc, San Diego, CA 92130 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 07期

关键词：

MYC; bromodomain; BRD4; PI3K; inhibitor; BET BROMODOMAIN INHIBITION; BREAST-CANCER; LEUKEMIA; BRD4; GENERATION; DISCOVERY; THERAPY; DESIGN; KINASE; FAMILY;

D O I：

10.1073/pnas.1613091114

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, andmarkedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dualactivity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.

引用

页码：E1072 / E1080

页数：9

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