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.
Highlights
Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced chimeric antigen receptor (CAR) T/NK cell immunotherapy
Our computational studies revealed that hydrogen-bonding functionalities around the C-ring subunit of the bryostatin scaffold, the C1 carbonyl, C26 hydroxyl and C19 hemiketal, are spatially preorganized by the A and B rings into a binding conformation that mimics protein kinase C (PKC)’s a b c
To investigate synthetic bryostatin 1 and bryostatin analogs as adjuvant leads for CD22-targeted CAR T therapy, we developed an in vitro assay for bryostatin-induced increased CD22 surface expression in acute lymphoblastic leukemia (ALL) using NALM6 cells
Summary
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. Several pre-clinical and clinical studies have reported that bryostatin 1 can alter the immunophenotype and increase the immunogenicity of cancer cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma (NHL)[17,26,27,28,29,30,31] These and related studies by a Spaner–Wender collaboration on CLL antigen expression and by a Zack–Marsden–Wender collaboration on CD69 expression in CD4+ T cells, the latter related to HIV eradication, indicate that PKC modulators can enhance expression and persistence of certain antigens, potentially enhancing a variety of (neo)antigen-targeted therapies[17,30,32,33,34]. Ramakrishna et al.[31] recently demonstrated that natural bryostatin
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