MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
Department of Pathlogy & Laboratory Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Immunology. 2023 Oct;170(2):230-242. doi: 10.1111/imm.13671. Epub 2023 Jun 1.
Antibody inhibitors that block PD-1/PD-L1 interaction have been approved for oncological clinics, yielding impressive treatment effects. Small molecules inhibiting PD-1 signalling are at various stages of development, given that small molecular drugs are expected to outperform protein drugs in several ways. Currently, a significant portion of these small molecular inhibitors achieve this purpose by binding to a limited region of the PD-L1 protein, thereby limiting the choice of chemical structures. Alternative strategies for developing small-molecular PD-1 inhibitors are urgently needed to broaden the choice of chemical structures. Here, we report that 6-mercaptopurine (6-MP) inhibits PD-1 signalling, activates T cell function in vitro and in vivo and shrinks tumours by activating cytotoxic T cells. Mechanistically, 6-MP potently inhibited PD-1 signalling by blocking the recruitment of SHP2 by PD-1. Considering that 6-MP is a chemotherapeutic agent already approved by the FDA for childhood leukaemia, our work revealed a novel anti-tumour mechanism for this drug and suggests that 6-MP warrants further clinical evaluation for other tumour types.
抗体抑制剂可阻断 PD-1/PD-L1 相互作用，已被批准用于肿瘤临床，产生显著的治疗效果。小分子 PD-1 信号抑制剂正处于不同的开发阶段，因为小分子药物有望在多个方面优于蛋白药物。目前，这些小分子抑制剂中的很大一部分通过与 PD-L1 蛋白的有限区域结合来达到这一目的，从而限制了化学结构的选择。因此，迫切需要开发小分子 PD-1 抑制剂的替代策略，以拓宽化学结构的选择。在这里，我们报告 6-巯基嘌呤（6-MP）可抑制 PD-1 信号，通过激活细胞毒性 T 细胞，在体外和体内激活 T 细胞功能，并缩小肿瘤。从机制上讲，6-MP 通过阻断 PD-1 募集 SHP2 来强力抑制 PD-1 信号。考虑到 6-MP 是一种已被 FDA 批准用于儿童白血病的化疗药物，我们的工作揭示了该药物的一种新的抗肿瘤机制，并表明 6-MP 值得进一步对其他肿瘤类型进行临床评估。
