Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

被引：367

作者：

Han, Huiying ^{[1
]}

Jain, Atul D. ^{[2
]}

Truica, Mihai I. ^{[1
]}

Izquierdo-Ferrer, Javier ^{[2
]}

Anker, Jonathan F. ^{[1
]}

Lysy, Barbara ^{[1
]}

Sagar, Vinay ^{[1
]}

Luan, Yi ^{[1
]}

Chalmers, Zachary R. ^{[1
]}

Unno, Kenji ^{[1
]}

Mok, Hanlin ^{[1
]}

Vatapalli, Rajita ^{[1
]}

Yoo, Young A. ^{[1
]}

Rodriguez, Yara ^{[1
]}

Kandela, Irawati ^{[3
]}

Parker, J. Brandon ^{[4
]}

Chakravarti, Debabrata ^{[4
,5
,6
]}

Mishra, Rama K. ^{[2
,6
]}

Schiltz, Gary E. ^{[2
,5
,6
]}

Abdulkadir, Sarki A. ^{[1
,5
,7
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA

[2] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Evanston, IL 60208 USA

[3] Northwestern Univ, Ctr Dev Therapeut, Evanston, IL 60208 USA

[4] Northwestern Univ, Feinberg Sch Med, Dept OB GYN, Div Reprod Sci Med, Chicago, IL 60611 USA

[5] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[6] Northwestern Univ, Feinberg Sch Med, Dept Pharmacol, Chicago, IL 60611 USA

[7] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA

来源：

CANCER CELL | 2019年 / 36卷 / 05期

关键词：

CELL-CYCLE; PD-L1; EXPRESSION; DNA-BINDING; CANCER; TARGET; PHARMACOKINETICS; IDENTIFICATION; INACTIVATION; ONCOPROTEIN; METABOLISM;

D O I：

10.1016/j.ccell.2019.10.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-moleculeMYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

引用

页码：483 / +

页数：30

共 57 条

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