Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions
Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions
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DOI：
10.3390/ijms21103639
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Miyatake, Hideyuki
中科院分区：
文献类型：
--
作者：
Kim, Eun-Hye;Kawamoto, Masuki;Miyatake, Hideyuki
单克隆抗体（mab）抑制免疫检查点分子（如程序性细胞死亡1 （PD-1）及其配体PD-L1）之间的相互作用，使癌症免疫治疗发生了革命性的变化。然而，基于单克隆抗体的药物存在一些缺点，包括肿瘤穿透性差和生产成本高，这些都有可能被小分子药物所克服。BMS-8是一种有效的小分子药物，可诱导PD-L1的同二聚化，从而抑制其与PD-1的结合。我们的实验系统显示BMS-8抑制PD-1/PD-L1相互作用的IC50为7.2 μ m，为了提高IC50值，我们在BMS-8分子结构的基础上通过硅模拟设计合成了一个小分子。结果，我们成功制备了IC50为1.5 μ M的联苯偶联溴酪氨酸(X)，比BMS-8提高了约5倍。我们进一步制备了X的氨基酸偶联物（氨基-X），以阐明氨基-X的对接方式与IC50值之间的关系。结果表明，PD-L1同型二聚体口袋中BMS-8中氨基x的位移与IC50值相关。这一观察结果为我们提供了进一步了解如何衍生X以获得更好的抑制效果。
Cancer immunotherapy has been revolutionized by the development of monoclonal antibodies (mAbs) that inhibit interactions between immune checkpoint molecules, such as programmed cell-death 1 (PD-1), and its ligand PD-L1. However, mAb-based drugs have some drawbacks, including poor tumor penetration and high production costs, which could potentially be overcome by small molecule drugs. BMS-8, one of the potent small molecule drugs, induces homodimerization of PD-L1, thereby inhibiting its binding to PD-1. Our assay system revealed that BMS-8 inhibited the PD-1/PD-L1 interaction with IC50 of 7.2 mu M. To improve the IC50 value, we designed and synthesized a small molecule based on the molecular structure of BMS-8 by in silico simulation. As a result, we successfully prepared a biphenyl-conjugated bromotyrosine (X) with IC50 of 1.5 mu M, which was about five times improved from BMS-8. We further prepared amino acid conjugates of X (amino-X), to elucidate a correlation between the docking modes of the amino-Xs and IC50 values. The results suggested that the displacement of amino-Xs from the BMS-8 in the pocket of PD-L1 homodimer correlated with IC50 values. This observation provides us a further insight how to derivatize X for better inhibitory effect.