设计的 PKC 调节剂的合成与评价，以增强癌症免疫治疗。
Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.
机构信息
Departments of Chemistry and of Chemical and Systems Biology, Stanford University, Stanford, CA, 94305, USA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
出版信息
Nat Commun. 2020 Apr 20;11(1):1879. doi: 10.1038/s41467-020-15742-7.
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.
原肌球蛋白 1 是一种海洋天然产物，正在研究用于艾滋病根除、治疗神经紊乱和增强 CAR T/NK 细胞免疫疗法。尽管原肌球蛋白 1 具有很有前途的活性，但它既不是为治疗人类疾病而进化也不是为治疗人类疾病而优化的。在这里，我们报告了几种与原肌球蛋白 1 密切相关的类似物的设计、合成和生物学评价。我们使用面向功能的合成方法，合成了一系列设计为保持与原肌球蛋白靶蛋白激酶 C（PKC）亲和力的原肌球蛋白类似物，同时能够探索它们不同的生物学功能。我们的后期多样化策略提供了一种高效获得原肌球蛋白类似物文库的途径，根据我们的设计，这些类似物保留了对 PKC 的亲和力，但表现出不同的 PKC 易位动力学。我们进一步证明，某些类似物能有效增加 CD22 的细胞表面表达，CD22 是治疗白血病的一种很有前途的 CAR T 细胞靶标，突出了原肌球蛋白类似物在增强靶向免疫疗法方面的临床潜力。
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