Drugging MYCN through an Allosteric Transition in Aurora Kinase A

作者：Gustafson William Clay; Meyerowitz Justin Gabriel; Nekritz Erin A; Chen Justin; Benes Cyril; Charron Elise; Simonds Erin F; Seeger Robert; Matthay Katherine K; Hertz Nicholas T; Eilers Martin; Shokat Kevan M; Weiss William A^*

来源：Cancer Cell, 2014, 26(3): 414-427.

DOI：10.1016/j.ccr.2014.07.015

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.

• 出版日期2014-9-8