Abstract PR08: Drugging MYCN protein stability through an allosteric transition in Aurora kinase A

Abstract

Abstract MYC family proteins represent a critical node in oncogenesis across a wide range of pediatric and adult cancers. This is particularly true in neuroblastoma, where amplification of MYCN confers an especially 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 allosteric inhibitors that disrupts the native conformation of Aurora A and causes degradation of MYCN protein across MYCN-expressing neuroblastoma cell lines. We compare co-crystal structures with structure-activity relationships across multiple inhibitors and chemotypes to delineate an Aurora A conformation-specific effect on proteolytic degradation of MYCN protein, which is driven markedly by conformation disrupting inhibitors, and impacted more modestly by current clinical Aurora Kinase A inhibitors, which disrupt the kinase structure less efficiently. Using functional assays of apoptosis, cell cycle, and proliferation we further define a distinct MYCN-specific effect distinguishing it from simple inhibition of mitosis by conventional Aurora kinase inhibitors. This new class of conformation disrupting inhibitors, which block stabilizing interactions between Aurora A and MYCN, represents a novel strategy to target MYCN-driven cancers. This abstract is also presented as Poster B46. Citation Format: W. Clay Gustafson, Justin G. Meyerowitz, Erin A. Nekritz, Elise Charron, Katherine K. Matthay, Nicholas T. Hertz, Martin Eilers, Kevan M. Shokat, William A. Weiss. Drugging MYCN protein stability through an allosteric transition in Aurora kinase A. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR08.