p53蛋白是人体内十分重要的肿瘤抑制因子,通过调节细胞周期阻滞、诱导细胞凋亡等作用发挥肿瘤抑制功能。突变后的p53蛋白不仅具有显性负性效应(dominant negative effect,DN)抑制野生型p53蛋白功能,而且还通过功能获得性效应(gain of function,GOF)调节细胞代谢、侵袭、迁移等方式促进肿瘤的发生。p53蛋白在超过50%的肿瘤组织中发生突变,是肿瘤细胞区别于正常细胞的一个特异性药物靶点。因此,针对突变p53蛋白开发新型抗癌药物一直是研究的热点。长期以来,由于突变p53蛋白表面较为光滑,缺乏药物结合口袋,使其被认为是一个不可成药的靶点。随着高通量筛选技术的发展以及对突变p53蛋白结构的深入了解,许多靶向突变p53蛋白的小分子化合物被报道并在体外展现出较好的抗肿瘤活性,多款基于突变p53蛋白研发的化合物已经进入临床试验阶段。本文就靶向p53蛋白治疗肿瘤的直接和间接策略进行综述,重点针对突变p53蛋白重激活剂与降解突变p53蛋白的小分子化合物作用机制进行梳理,以期为后续开发靶向突变p53蛋白药物的创新提供帮助。
Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation.Identifying molecular glues is challenging.There is a scarcity of target-specific upregulating molecular glues,which are highly anticipated for numerous targets,including P53.P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases,whereas deubiquitinases(DUBs)remove polyubiquitination conjugates to counteract these E3ligases.Thus,small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination.Here,using small-molecule microarray-based technology and unbiased screening,we identified three potential molecular glues that may tether P53 to the DUB,USP7,and elevate the P53 level.Among the molecular glues,bromocriptine(BC)is an FDA-approved drug with the most robust effects.BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7.Consistent with P53 upregulation in cancer cells,BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model.In summary,we established a potential screening platform and identified potential molecular glues upregulating P53.Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.
