Optimizing Conformation Disrupting Aurora Kinase Inhibitors to Treat MYCN Amplified Neuroblastoma

Background

Neuroblastoma is among the most common and deadly childhood cancers. Amplification of the transcription factor oncogene MYCN drives a large subset of high risk neuroblastoma tumors and represents an excellent candidate for therapeutic intervention. MYCN interacts with the protein Aurora Kinase A. We have recently developed a novel "conformation disrupting" inhibitor of Aurora Kinase A, CD532, which potently drives the loss of MYCN. This pilot compound has a unique mechanism of action, but is not fully optimized to maximize MYCN loss or for clinical use in patients. In collaboration with Kevan Shokat, a molecular pharmacologist at UCSF, we are developing a novel series of optimized drugs which bind to Aurora Kinase A and more potently disrupt its conformation to drive MYCN loss.

Project Goal

We plan to develop inhibitors which "dial out" toxic Aurora Kinase A activity and finesse more potent MYCN degradation in neuroblastoma to optimize therapeutic efficacy. Newly synthesized drugs and drug series from the Shokat lab will be tested for optimal biochemical properties, including the ability to potently disrupt the MYCN/Aurora A complex, and optimal pharmacokinetic properties like absorption and maintenance of high concentrations in the blood.