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PROTACs as Degraders of RSK2

Joel Kawakami, PhD headshot
Joel Kawakami, PhD

RESEARCH SUMMARY: This proposal focuses on the discovery and investigation of novel compounds as potential drugs for the treatment of cancer through the degradation of RSK, (Ribosomal Protein S6 Kinase), the primary Ras Signaling mediator of integrins and cell migration.  The project will center on the discovery of novel quinoxaline war-heads as full PROTACs (Proteolysis Targeting Chimera) (MOE), a molecular modeling software. The design of these PROTACs will investigate varying length alkyl and PEG (polyethylene glycol) linkers for attachment of the quinoxaline war-head to an E3 recruiting ligase – Lenalidomide. The use of PROTACs for RSK2 degradation is completely novel.

The immediate goal will be to provide sufficient preliminary data for PROTACs as degraders of RSK2 for treatment of cancer that leads to a successful AREA R15 grant application.  These PROTACs will be designed together with Dr. Ramos, then synthesized in Dr. Kawakami’s CUH laboratory.  The design will be based on ligand to protein docking of PROTACs using MOE.

All PROTACs synthesized will be fully characterized (1H & 13C-NMR and High-Resolution Mass Spectroscopy) then biologically evaluated in the laboratory of Dr. Ramos for RSK inhibitory potency/efficacy in purified protein and Cell-Based Assays.

BIOGRAPHY: Before coming to Chaminade, Dr. Kawakami formed the company Kawakami, LLC, of West Milford, NJ, to provide a rapid lead/drug optimization technology service for clients utilizing novel molecular descriptors that are highly predictive of a compound’s affinity for a molecular target of interest. From 2001-2005, Dr. Kawakami was employed by Imclone Systems Inc., New York, NY, as an Associate Director, for the Chemistry Department. Dr. Kawakami was employed by the Synaptic Pharmaceutical Corp., Paramus, NJ as a Senior Scientist, Discovery Chemistry (2000-2001). Dr. Kawakami thus brings real-world experience in the pharma industry to his general chemistry, biochemistry and pharmacology courses. He is the adviser for Chemistry minors and is an investigator on a funded NIH R01 grant for his research work in molecular dynamic modeling for protein kinases. He is an affiliate member of the University of Hawaii Cancer Center and a past Chair of the ACS Hawaii Chapter. He has previously been an NIH INBRE investigator and is an avid supervisor of undergraduate research internships.

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