PD-1小分子抑制剂的开发与其作用分子机理和肺癌治疗的研究

Lung cancer is the leading cause of cancer-related deaths, and is a particularly serious public health issue in China. Chemotherapy and targeted therapy are the mainstay of current lung cancer therapy. However, both are limited by either toxicity or efficacy, and inevitable relapse in patients. Effective alternative therapies are desperately needed in lung cancer clinics. Recently, immuno-checkpoint inhibitors have demonstrated their ability to activate T cells to kill target cancer cells and shrink tumors in vivo. Several antibodies have been approved for clinical use. We propose to develop small molecular inhibitors against PD-1, antibodies against which have been well confirmed to have drastic treatment effect on cancer patients. For this purpose, we have established a high-throughput screening system. Preliminary screening of 40,000 compounds yields some candidate inhibitors. We have also established another high-throughput screening system based on our ability to evaluate IL-2 secretion by activated T cells. Using this system, we confirmed 5 compounds (including 1 FDA approved drug) of the candidates from first screening having strong ability to enhance T cell response through blocking PD-1 signaling. We propose to finish screening of 300,000 compounds (including nearly 3,000 FDA approved drugs) in the chemical library of NIBS. We propose to study the molecular mechanism underlying the candidate inhibitors’ ability to inhibit signaling elicited by PD-1. We propose to evaluate inhibitors’ ability to enhance the ability of T cells to kill target cell in vitro and in vivo. We will also evaluate the in vivo efficacy of these inhibitors to treat lung cancer using transgenic mouse model.

肺癌是全球范围内对人类健康威胁最大的肿瘤，中国的肺癌问题尤其严重。现行的化疗和靶向治疗在肺癌中存在一些问题。开发针对肺癌有效治疗方法是一个噬待解决的临床问题。近年来，人们能通过抑制T细胞的check-point（如PD-1）来激活体内的免疫细胞，杀伤肿瘤细胞而达到治疗目的。目前批准应用于临床的药物都是抗体。我们提议开发PD-1的小分子抑制剂。为此，我们建立了一个高效筛选PD-1小分子抑制剂的平台，并初步筛选4万个小分子化合物，并产生了一些小分子抑制剂。我们建立了一个基于T细胞分泌IL-2的复筛平台，复筛的结果显示筛选5个初筛产生的候选小分子能显著提高T细胞的应答能力。我们提议对北京生命科学研究所的30万个化合物进行全面筛选，我们将对小分子的抑制机理进行深入研究，并评估其体内和体外的提高T细胞杀伤肿瘤细胞的活力，我们还将评估这些筛选产生的小分子抑制剂在体内治疗肺癌的能力。

PD-1的药物在癌症治疗中展现出强大的治疗能力，但目前我国已进入临床和正在审批的抑制剂都是抗体，其生产、存储、运输及病人给药方面都有较大的局限，另外，目前在临床中应用的抑制剂都通过抑制PD-1/PD-L1的结合，思路比较狭窄，需要有新的策略。.我实验室通过前期的研究，发现抑制PD-1在胞内招募SHP2这一步骤能有效的抑制PD-1的信号传导，激活T细胞的细胞毒性功能。同时，我实验室鉴定了一些具有较强抑制PD-1招募SHP2能力的小分子。.经过前期研究，我们发表了7篇SCI论文，转让1项专利，培养了1名博士后，2名博士，2名硕士。