| First Author | Gustafson WC | Year | 2014 |
| Journal | Cancer Cell | Volume | 26 |
| Issue | 3 | Pages | 414-427 |
| PubMed ID | 25175806 | Mgi Jnum | J:214800 |
| Mgi Id | MGI:5604026 | Doi | 10.1016/j.ccr.2014.07.015 |
| Citation | Gustafson WC, et al. (2014) Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26(3):414-27 |
| abstractText | 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. |
