Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Clayton Hardman, Stephen Ho, Akira Shimizu, Quang Luu-Nguyen, Jack L. Sloane, Mohamed S. A. Soliman, Matthew D. Marsden (), Jerome A. Zack () and Paul A. Wender ()
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Clayton Hardman: Stanford University
Stephen Ho: Stanford University
Akira Shimizu: Stanford University
Quang Luu-Nguyen: Stanford University
Jack L. Sloane: Stanford University
Mohamed S. A. Soliman: University of California, Los Angeles
Matthew D. Marsden: University of California, Los Angeles
Jerome A. Zack: University of California, Los Angeles
Paul A. Wender: Stanford University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin’s target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.

Date: 2020
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DOI: 10.1038/s41467-020-15742-7

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