Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1
Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1
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DOI：
10.1021/acs.jmedchem.7b00293
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发表时间：
2017-07-13
影响因子：
7.3
通讯作者：
Holak, Tad A.
中科院分区：
文献类型：
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作者：
Guzik, Katarzyna;Zak, Krzysztof M.;Holak, Tad A.
用单抗阻断PD-1/PD-L1免疫检查点通路，为肿瘤治疗提供了重要进展。基于抗体的免疫疗法有许多缺点，如抗体成本高，半衰期有限，以及免疫原性。能够克服这些缺陷的小分子PD-1/PD-L1抑制剂的开发进展缓慢，因为这一途径的结构信息不完整。百时美施贵宝(Bristol-Myers Squibb)最近披露了第一种PD-1/PD-L1抑制剂。在这里，我们介绍了这两类抑制剂的核磁共振和X射线表征。Pd-L1/抑制剂复合体的X射线结构表明，一个抑制剂分子位于PD-L1均二聚体的中心，填充了两个PD-L1分子之间的深疏水通道状口袋。(2-甲基-3-联苯基)甲醇的衍生物表现出通道一侧封顶的结构，而基于[3-(2，3-dihydro-1，4-benzodioxin-6-yl)-2-methylphenyl]methanol的化合物诱导扩大的相互作用界面，导致通过PD-L1二聚体的开放的正面-背面隧道。
Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol induce an enlarged interaction interface that results in the open face-back tunnel through the PD-L1 dimer.