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Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-16 , DOI: 10.1021/acs.jmedchem.0c01260 Magdalena Konieczny 1 , Bogdan Musielak 1 , Justyna Kocik 1 , Lukasz Skalniak 1 , Dominik Sala 1 , Miroslawa Czub 1 , Katarzyna Magiera-Mularz 1 , Ismael Rodriguez 1 , Maja Myrcha 1 , Malgorzata Stec 2 , Maciej Siedlar 2 , Tad A Holak 1 , Jacek Plewka 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-16 , DOI: 10.1021/acs.jmedchem.0c01260 Magdalena Konieczny 1 , Bogdan Musielak 1 , Justyna Kocik 1 , Lukasz Skalniak 1 , Dominik Sala 1 , Miroslawa Czub 1 , Katarzyna Magiera-Mularz 1 , Ismael Rodriguez 1 , Maja Myrcha 1 , Malgorzata Stec 2 , Maciej Siedlar 2 , Tad A Holak 1 , Jacek Plewka 1
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Immune checkpoint blockade is one of the most promising strategies of cancer immunotherapy. However, unlike classical targeted therapies, it is currently solely based on expensive monoclonal antibodies, which often inflict immune-related adverse events. Herein, we propose a novel small-molecule inhibitor targeted at the most clinically relevant immune checkpoint, PD-1/PD-L1. The compound is capable of disrupting the PD-1/PD-L1 complex by antagonizing PD-L1 and, therefore, restores activation of T cells similarly to the antibodies, while being cheap in production and possibly nonimmunogenic. The final compound is significantly smaller than others reported in the literature while being nontoxic to cells even at high concentrations. The scaffold was designed using a structure–activity relationship screening cascade based on a new antagonist-induced dissociation NMR assay, called the weak-AIDA-NMR. Weak-AIDA-NMR finds true inhibitors, as opposed to only binders to the target protein, in early steps of lead compound development, and this process makes it less time and cost consuming.
中文翻译：
PD-1 / PD-L1免疫检查点的基于二溴的小分子抑制剂。
免疫检查站封锁是癌症免疫疗法最有希望的策略之一。但是，与经典的靶向疗法不同，它目前仅基于昂贵的单克隆抗体，通常会产生免疫相关的不良事件。在本文中，我们提出了一种针对最临床相关的免疫检查点PD-1 / PD-L1的新型小分子抑制剂。该化合物能够通过拮抗PD-L1而破坏PD-1 / PD-L1复合物，因此，与抗体类似，恢复了T细胞的活化，同时生产廉价并且可能具有非免疫原性。最终化合物显着小于文献中报道的其他化合物，即使对高浓度的化合物也对细胞无毒。该支架是使用结构-活性关系筛选级联设计的，该级联基于一种新的拮抗剂诱导的离解NMR分析，称为弱AIDA-NMR。弱AIDA-NMR在铅化合物开发的早期步骤中发现了真正的抑制剂，而不是仅与目标蛋白结合的抑制剂，并且该过程减少了时间和成本。
更新日期：2020-10-08
中文翻译：
PD-1 / PD-L1免疫检查点的基于二溴的小分子抑制剂。
免疫检查站封锁是癌症免疫疗法最有希望的策略之一。但是，与经典的靶向疗法不同，它目前仅基于昂贵的单克隆抗体，通常会产生免疫相关的不良事件。在本文中，我们提出了一种针对最临床相关的免疫检查点PD-1 / PD-L1的新型小分子抑制剂。该化合物能够通过拮抗PD-L1而破坏PD-1 / PD-L1复合物，因此，与抗体类似，恢复了T细胞的活化，同时生产廉价并且可能具有非免疫原性。最终化合物显着小于文献中报道的其他化合物，即使对高浓度的化合物也对细胞无毒。该支架是使用结构-活性关系筛选级联设计的，该级联基于一种新的拮抗剂诱导的离解NMR分析，称为弱AIDA-NMR。弱AIDA-NMR在铅化合物开发的早期步骤中发现了真正的抑制剂，而不是仅与目标蛋白结合的抑制剂，并且该过程减少了时间和成本。
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