Editors' ChoiceCancer

Targeting the “Undruggable” MYCN

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Sci. Signal.  23 Sep 2014:
Vol. 7, Issue 344, pp. ec260
DOI: 10.1126/scisignal.2005928

The MYC family of transcription factors is as yet impossible to target pharmacologically due to their structure. Amplification of the gene encoding MYCN is a predictor of poor prognosis in neuroblastoma patients. MYCN is typically degraded by a phosphorylation- and ubiquitylation-dependent mechanism, which is prevented by its interaction with the mitotic kinase Aurora A. Gustafson et al. identified an allosteric inhibitor of Aurora A that prevented this stabilizing interaction. Whereas most catalytic inhibitors of Aurora A had no effect on MYCN, CD532 (the lead compound from a screen of conformation-disrupting compounds) inhibited the kinase activity of Aurora A and dose-dependently decreased the abundance of MYCN in two neuroblastoma cell lines and in xenografts in mice. CD532 did not alter the abundance of Aurora A. The toxicity of CD532 in cells was associated with S-phase arrest and was directly proportional to the decrease in MYCN abundance. Expression of a nonphosphorylatable mutant of MYCN in SHEP neuroblastoma cells partially prevented the CD532-induced degradation of total MYCN, suggesting that CD532 may promote the phosphorylation-dependent degradation of MYCN. Structure analysis of crystalized CD532-bound or unbound Aurora A indicated that CD532 binding in the hinge region of the kinase caused the usually rigid N-terminal domain to rotate and shift, displacing the critical Arg residue from the Thr residue in the active site. Thus, the findings suggest that this conformation-altering inhibitor of Aurora A may be a way to target MYCN and provide therapeutic benefit to patients.

W. C. Gustafson, J. G. Meyerowitz. E. A. Nekritz, J. Chen, C. Benes, E. Charron, E. F. Simonds, R. Seeger, K. K. Matthay, N. T. Hertz, M. Eilers, K. M. Shokat, W. A. Weiss, Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26, 414–427 (2014). [PubMed]