Chemical control over immune recognition: a class of antibody-recruiting small molecules that target prostate cancer.
Chemical control over immune recognition: a class of antibody-recruiting small molecules that target prostate cancer.
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DOI：
10.1021/ja906844e
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发表时间：
2009-12-02
影响因子：
15
通讯作者：
Spiegel, David A.
中科院分区：
文献类型：
--
作者：
Murelli, Ryan P.;Zhang, Andrew X.;Michel, Julien;Jorgensen, William L.;Spiegel, David A.
前列腺癌是美国男性人群中癌症相关死亡的第二大原因，社会迫切需要治疗这种疾病的新方法。在这里，我们报告了一类双功能小分子的设计，合成和生物学评价，称为靶向前列腺癌的抗体募集分子（ARM-Ps），增强了人类免疫系统对前列腺癌细胞的识别。ARM-P衍生物是通过晶体学数据的计算分析合理设计的，我们在这里证明这些材料能够：（1）以高亲和力结合PSMA（2）在抗DNP抗体、ARM-P和LNCaP人前列腺癌细胞之间形成三元复合物的模板，和（3）在人效应细胞存在下介导LNCaP细胞的抗体依赖性杀伤。这份手稿描述了基本化学原理在设计一类具有高治疗潜力的新型分子中的应用。我们相信，这种基于小分子的一般策略可以为治疗癌症和其他疾病提供新的方向。
Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biological evaluation of a class of bifunctional small molecules, called antibody-recruiting molecules targeting prostate-cancer (ARM-Ps), that enhance the recognition of prostate cancer cells by the human immune system. ARM-P derivatives were designed rationally via the computational analysis of crystallographic data, and we demonstrate here that these materials are able to: (1) bind PSMA with high affinity (high pM to low nM), (2) template the formation of ternary complexes between anti-DNP antibodies, ARM-P, and LNCaP human prostate cancer cells, and (3) mediate the antibody-dependent killing of LNCaP cells in the presence of human effector cells. This manuscript describes the application of fundamental chemical principles to the design of a novel class of molecules with high therapeutic potential. We believe that this general small-molecule-based strategy could give rise to novel directions in treating cancer and other diseases.
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