Drugging MYCN through an Allosteric Transition in Aurora Kinase A

被引：215

作者：

Gustafson, William Clay ^{[1
,5
]}

Meyerowitz, Justin Gabriel ^{[2
,3
,4
,5
]}

Nekritz, Erin A. ^{[1
,5
]}

Chen, Justin ^{[2
,3
]}

Benes, Cyril ^{[8
]}

Charron, Elise ^{[1
,2
,3
,5
]}

Simonds, Erin F. ^{[2
,3
,5
]}

Seeger, Robert ^{[9
]}

Matthay, Katherine K. ^{[1
,5
]}

Hertz, Nicholas T. ^{[4
]}

Eilers, Martin ^{[7
]}

Shokat, Kevan M. ^{[4
,6
]}

Weiss, William A. ^{[1
,2
,3
,5
]}

机构：

[1] Univ Calif San Francisco, UCSF Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[6] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA

[7] Univ Wurzburg, Theodor Boveri Inst, Bioctr, D-97074 Wurzburg, Germany

[8] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Charlestown, MA 02114 USA

[9] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA

来源：

CANCER CELL | 2014年 / 26卷 / 03期

关键词：

SMALL-MOLECULE INHIBITOR; N-MYC; THERAPEUTIC TARGETS; HISTONE H3; DFG FLIP; A KINASE; NEUROBLASTOMA; MECHANISM; MLN8237; PHOSPHORYLATION;

D O I：

10.1016/j.ccr.2014.07.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity.

引用

页码：414 / 427

页数：14

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