Abstract 2688: Drugging MYCN through an allosteric transition in Aurora A kinase

Abstract

Abstract MYC genes contribute to a range of cancers including neuroblastoma, where amplification of MYCN confers a poor prognosis. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora kinase A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and causes degradation of MYCN protein across MYCN-expressing neuroblastoma cell lines. Comparison of co-crystal 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. This new class of inhibitors, which disrupts stabilizing interactions between Aurora A and MYCN, represents candidate agents to target MYCN-driven and potentially MYC-driven cancers. Citation Format: William C. Gustafson, Justin G. Meyerowitz, Erin A. Nekritz, Elise A. Charron, Yvan Chanthery, Erin Simonds, Katherine Matthay, Nicholas Hertz, Kevan Shokat, William A. Weiss. Drugging MYCN through an allosteric transition in Aurora A kinase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2688. doi:10.1158/1538-7445.AM2014-2688