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Drugging MYCN through an allosteric transition in Aurora kinase A.

ABSTRACT: 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.

SUBMITTER: Gustafson WC

PROVIDER: S-EPMC4160413 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Drugging MYCN through an allosteric transition in Aurora kinase A.

Gustafson William Clay WC Meyerowitz Justin Gabriel JG Nekritz Erin A EA Chen Justin J Benes Cyril C Charron Elise E Simonds Erin F EF Seeger Robert R Matthay Katherine K KK Hertz Nicholas T NT Eilers Martin M Shokat Kevan M KM Weiss William A WA

Cancer cell 20140828 3

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 ...[more]

PMID: 25175806

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