Research progress of p53-MDM2/MDM4 related anti-tumor drugs and their mechanisms / 中国肿瘤生物治疗杂志

@#[摘 要] 由抑癌基因TP53编码的p53是体内最重要的抑癌因子之一。MDM2/MDM4是p53的负向调控因子，通过p53-MDM2/MDM4负反馈环路调控p53功能。几乎所有肿瘤均存在p53异常，主要包括p53突变和MDM2/MDM4扩增引起的p53失活。p53相关药物研发一直是肿瘤研究中的热点，然而，直到最近10年才研发出相对成熟的药物。目前，以逆转p53失活为目标的药物研发存在以下几种设计思路：（1）诱导突变p53恢复野生型功能，如PRIMA-1/PRIMA-1MET、COTI-2；（2）促进突变p53降解，如Ganetespib、伏立诺他；（3）阻断MDM2/MDM4，如RG7388、ALRN-6924等。上述药物均已进入临床试验，其中伏立诺他、PRIMA-1MET和ALRN-6924已分别在卵巢癌及骨髓增生异常综合征、皮肤T细胞淋巴瘤、急性髓系白血病中取得较好的疗效。进一步阐明p53-MDM2/MDM4环路异常在肿瘤中的作用机制，对于未来研发p53相关抗肿瘤药物以及指导临床用药具有重要意义。

Advances in inhibitors of MDM2 and MDM4 / 中国药科大学学报

@#The protein p53 plays an important role in the regulation of DNA repair, cell cycle arrest, apoptosis, senescence, autophagy and metabolism. MDM2 and MDM4 are the key negative regulatory proteins of p53. Inhibition of MDM2 and MDM4 has become a research hotspot in cancer therapy. Currently, seven MDM2 inhibitors(RG7112, MI-77301, RG7388, AMG232, CGM097, MK-8242, DS-3032b)and one MDM2/MDM4 dual inhibitor(ALRN-6924)have entered clinical trials. This paper highlights small molecule discovery, pharmacological activities and clinical research advances of MDM2 inhibitors in clinical trials, in addition, this review introduces research advances of MDM2/MDM4 dual inhibitors.