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Drugging MYCN through an allosteric transition in Aurora kinase A.

Cancer cell | 2014

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.

Pubmed ID: 25175806 RIS Download

Research resources used in this publication

None found

Antibodies used in this publication

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: F30CA174154
  • Agency: NCI NIH HHS, United States
    Id: U01 CA176287
  • Agency: NHGRI NIH HHS, United States
    Id: U54 HG006097
  • Agency: NCI NIH HHS, United States
    Id: R01 CA159859
  • Agency: NCI NIH HHS, United States
    Id: P30 CA082103
  • Agency: NINDS NIH HHS, United States
    Id: K08NS079485
  • Agency: NCI NIH HHS, United States
    Id: L40 CA153057
  • Agency: NCI NIH HHS, United States
    Id: R01CA102321
  • Agency: NCI NIH HHS, United States
    Id: R01 CA148699
  • Agency: NCI NIH HHS, United States
    Id: R01CA148699
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM064337
  • Agency: NCI NIH HHS, United States
    Id: T32 CA128583
  • Agency: NCI NIH HHS, United States
    Id: P30CA82103
  • Agency: NINDS NIH HHS, United States
    Id: K08 NS079485
  • Agency: NCI NIH HHS, United States
    Id: R01 CA102321
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007618
  • Agency: NCI NIH HHS, United States
    Id: P01 CA081403
  • Agency: NCI NIH HHS, United States
    Id: R01CA159859
  • Agency: NCI NIH HHS, United States
    Id: P01CA081403
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NHGRI NIH HHS, United States
    Id: 1U54HG006097-01
  • Agency: NCI NIH HHS, United States
    Id: F30 CA174154

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