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Drugging MYCN through an allosteric transition in Aurora kinase A.
- Source :
-
Cancer cell [Cancer Cell] 2014 Sep 08; Vol. 26 (3), pp. 414-427. Date of Electronic Publication: 2014 Aug 28. - Publication Year :
- 2014
-
Abstract
- 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.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Allosteric Regulation
Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Area Under Curve
Aurora Kinase A antagonists & inhibitors
Aurora Kinase A metabolism
Catalytic Domain
Cell Line, Tumor
Cell Survival drug effects
Crystallography, X-Ray
Humans
Mice
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Models, Molecular
N-Myc Proto-Oncogene Protein
Neuroblastoma pathology
Nuclear Proteins chemistry
Oncogene Proteins chemistry
Phenylurea Compounds chemistry
Phenylurea Compounds pharmacokinetics
Phosphorylation
Protein Processing, Post-Translational
Protein Structure, Secondary
Proteolysis
Pyrimidines chemistry
Pyrimidines pharmacokinetics
S Phase Cell Cycle Checkpoints drug effects
Structure-Activity Relationship
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Aurora Kinase A chemistry
Neuroblastoma drug therapy
Nuclear Proteins metabolism
Oncogene Proteins metabolism
Phenylurea Compounds pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 25175806
- Full Text :
- https://doi.org/10.1016/j.ccr.2014.07.015