Cancer cell, 2014-09, Vol.26 (3), p.414-427
2014
Details
- Autor(en) / Beteiligte
- Titel
- Drugging MYCN through an Allosteric Transition in Aurora Kinase A
- Ist Teil von
- Cancer cell, 2014-09, Vol.26 (3), p.414-427
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •A class of inhibitors disrupts the conformation of Aurora A and destabilizes MYCN•CD532 potently inhibits the activities of Aurora A and MYCN•CD532 blocks MYCN in vitro and in vivo, across tumor types Gustafson et al. develop Aurora A inhibitors that not only potently inhibit its kinase activity but also severely alter its conformation, the latter of which reduces Aurora A-MYCN interaction, leading to enhanced MYCN degradation. This may represent a useful approach for targeting MYCN for cancer therapy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccr.2014.07.015Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4160413
- Format
- –
- Schlagworte
- Allosteric Regulation, Animals, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacokinetics, Antineoplastic Agents - pharmacology, Area Under Curve, Aurora Kinase A - antagonists & inhibitors, Aurora Kinase A - chemistry, 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 - drug therapy, Neuroblastoma - pathology, Nuclear Proteins - chemistry, Nuclear Proteins - metabolism, Oncogene Proteins - chemistry, Oncogene Proteins - metabolism, Phenylurea Compounds - chemistry, Phenylurea Compounds - pharmacokinetics, Phenylurea Compounds - pharmacology, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Secondary, Proteolysis, Pyrimidines - chemistry, Pyrimidines - pharmacokinetics, Pyrimidines - pharmacology, S Phase Cell Cycle Checkpoints - drug effects, Structure-Activity Relationship, Tumor Burden - drug effects, Xenograft Model Antitumor Assays