Drugging MYCN through an Allosteric Transition in Aurora Kinase A
Menée in vitro, cette étude décrit une nouvelle classe d'inhibiteurs qui, en perturbant la conformation de la protéine Aurora A, induit la dégradation de la protéine MYCN, une protéine impliquée dans le développement de divers cancers
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.