Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2

被引：645

作者：

Knutson, Sarah K. ^{[1
]}

Warholic, Natalie M. ^{[1
]}

Wigle, Tim J. ^{[1
]}

Klaus, Christine R. ^{[1
]}

Allain, Christina J. ^{[1
]}

Raimondi, Alejandra ^{[1
]}

Scott, Margaret Porter ^{[1
]}

Chesworth, Richard ^{[1
]}

Moyer, Mikel P. ^{[1
]}

Copeland, Robert A. ^{[1
]}

Richon, Victoria M. ^{[1
]}

Pollock, Roy M. ^{[1
]}

Kuntz, Kevin W. ^{[1
]}

Keilhack, Heike ^{[1
]}

机构：

[1] Epizyme Inc, Cambridge, MA 02139 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 19期

关键词：

epigenetic cancer therapy; EZH2; inhibitor; POLYCOMB; LYMPHOMA; CELLS; LEADS;

D O I：

10.1073/pnas.1303800110

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：

Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers. We report the discovery of a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity, (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide). The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells. Treatment of xenograft-bearing mice with (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide) leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers.

引用

页码：7922 / 7927

页数：6

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