Drugging MYCN through an allosteric transition in Aurora kinase A.
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.
Mesh Terms:
Allosteric Regulation, Animals, Antineoplastic Agents, Area Under Curve, Aurora Kinase A, Catalytic Domain, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Humans, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Models, Molecular, N-Myc Proto-Oncogene Protein, Neuroblastoma, Nuclear Proteins, Oncogene Proteins, Phenylurea Compounds, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Secondary, Proteolysis, Pyrimidines, S Phase Cell Cycle Checkpoints, Structure-Activity Relationship, Tumor Burden, Xenograft Model Antitumor Assays
Allosteric Regulation, Animals, Antineoplastic Agents, Area Under Curve, Aurora Kinase A, Catalytic Domain, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Humans, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Models, Molecular, N-Myc Proto-Oncogene Protein, Neuroblastoma, Nuclear Proteins, Oncogene Proteins, Phenylurea Compounds, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Secondary, Proteolysis, Pyrimidines, S Phase Cell Cycle Checkpoints, Structure-Activity Relationship, Tumor Burden, Xenograft Model Antitumor Assays
Cancer Cell
Date: Sep. 08, 2014
PubMed ID: 25175806
View in: Pubmed Google Scholar
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