Journal Article

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Marsden, Matthew D., Luu-Nguyen, Quang, Ho, Stephen, Hardman, Clayton, Wender, Paul A., Shimizu, Akira, Zack, Jerome A., Soliman, Mohamed S. A., Sloane, Jack L.

2020

Overview

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. Bryostatin 1 is a unique therapeutic lead, however its scarce natural sources have hampered its use in treatment of human disease. Here, the authors use a scalable synthesis of bryostatin 1 to make close-in analogs which potently induce increased cell surface expression holding potential for immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67/1059/2325 / 639/638/309/2132 / 639/638/403/933 / 639/638/549/975 / Affinity / Analogs / Bryostatins - biosynthesis / Bryostatins - chemistry / Bryostatins - pharmacology / Cancer immunotherapy / CD22 antigen / Cell Line, Tumor / Cell surface / Design / Divergence / Health services / HIV / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immunomodulation / Immunotherapy / Immunotherapy - methods / Kinases / Leukemia / Leukemia - drug therapy / Lymphocytes / Lymphocytes T / Models, Molecular / Modulators / multidisciplinary / Natural killer cells / Natural products / Neoplasms - drug therapy / Neurological diseases / Neuromodulation / Protein kinase C / Protein Kinase C - metabolism / Science / Science (multidisciplinary) / Sialic Acid Binding Ig-like Lectin 2 - metabolism / Synthesis / T-Lymphocytes / Translocation