Drugging MYCN through an allosteric transition in Aurora kinase A

William Clay Gustafson; Justin Gabriel Meyerowitz; Erin A Nekritz; Justin Chen; Cyril Benes; Elise Charron; Erin F Simonds; Robert Seeger; Katherine K Matthay; Nicholas T Hertz; Martin Eilers; Kevan M Shokat; William A Weiss

doi:10.1016/j.ccr.2014.07.015

Drugging MYCN through an allosteric transition in Aurora kinase A

Cancer Cell. 2014 Sep 8;26(3):414-427. doi: 10.1016/j.ccr.2014.07.015. Epub 2014 Aug 28.

Authors

Affiliations

¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
² Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02114, USA.
⁵ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Division of Hematology/Oncology, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #57, Los Angeles, CA 90027, USA.
⁸ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Würzburg, Germany.
¹⁰ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
¹¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Antineoplastic Agents
CD532 compound
MYCN protein, human
N-Myc Proto-Oncogene Protein
Nuclear Proteins
Oncogene Proteins
Phenylurea Compounds
Pyrimidines
AURKA protein, human
Aurora Kinase A

Associated data

PDB/4J8M
PDB/4J8N

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding