BM-1197诱导NHL细胞凋亡及其疗效与Bcl-2家族蛋白表达相关性研究

Bcl-2家族蛋白是细胞凋亡内源性途径的核心因子，抗凋亡蛋白及促凋亡蛋白通过BH结构域形成同源或异源二聚体控制凋亡的启动。Bcl-2在多种肿瘤中过表达，抑制细胞凋亡，成为新的肿瘤治疗靶点。既往研发的Bcl-2抑制剂，由于亲和力过低、特异性不足、广谱性不够等原因一直未能在临床使用。BH3结构域为Bcl-2家族成员促凋亡活性必不可少，是蛋白相互作用的核心和结构基础。国内首次研发的Bcl-2抑制剂BM-1197是BH3结构域高度类似物，具有结构新颖、亲和力高、特异性强等特点，其亲和力优于ABT-737/263。本研究拟开展BM-1197在非霍奇金淋巴瘤(NHL)中的抗肿瘤活性检测及其作用机制的探讨，并开展与常规化疗药物的联合用药研究，建立动物模型明确其体内抗肿瘤活性，进一步寻找可能的疗效预测生物标志物，为BM-1197在临床研究中患者选择提供参考，为开发新型Bcl-2抑制剂提供临床前数据。

Members of the Bcl-2 family constitute the critical effectors in intrinsic pathway of apoptosis. The homodimers or heterodimers formed by the interactions of pro-apoptotic and anti-apoptotic Bcl-2 proteins through BH domain control the initiation of apoptosis. Bcl-2 overexpresses in many types of tumors and promotes cell survival. Targeting Bcl-2 protein is the new strategy of tumor therapy. Many previously developed Bcl-2 inhibitors have low affinity and poor specificity therefore were not suitable for clinical applications. BH3 domain is the essential factor and key structure for the interactions of Bcl-2 family members in the regulation of apoptosis. The new Bcl-2 inhibitor designed and synthesized by our labs is a novel BH3 mimetic small molecule with high affinity and specificity, even better than ABT-737/263. The antitumor effect and mechanism of BM-1197 in NHL cell lines will be investigated in this study. Optimal combination with anticancer drugs and the antitumor effect in vivo will be also explored and the possible biomarkers to predict the efficacy of BM-1197 will be examined. This study will provide preclinical data for further development of Bcl-2 inhibitor.