a Department of Organic Chemistry, Faculty of Chemistry , Jagiellonian University , Krakow , Poland.
Expert Opin Ther Pat. 2019 Mar;29(3):151-170. doi: 10.1080/13543776.2019.1582645. Epub 2019 Mar 1.
MDM2 and MDMX proteins provide the inhibition of p53 tumor suppressor, thus allowing for accelerated mutation-driven cancer microevolution. A pharmacological blockade of MDM2/X-p53 interaction results in p53 reactivation in p53 cells, leading to cancer growth inhibition. Throughout the past 20 years, multiple chemical entities have been proposed to reactivate p53 by antagonizing MDM2/X proteins.
This manuscript reviews 2014-2018 therapeutic patents in the field of MDM2/X antagonists and is a continuation of previous reviews on similar matter. The patents covering the use of MDM2/X antagonists in drug combinations are also presented in this review, as they constitute an important trend in the field of cancer treatment with MDM2/X antagonists.
In the years 2014-2018, several previously-known chemical scaffolds have been further developed and disclosed. Importantly, in the same time period, many lead compounds have entered clinical trials for the treatment of cancer patients. Meanwhile, several important reports have pointed to serious limitations of anticancer properties of MDM2 antagonists. As a result, many efforts have been made to seek for positive, synergistic therapeutic effects of combined anti-cancer treatment strategies. One recent example is a dual targeting of MDM2 and additional protein targets by utilizing the PROTAC technology.
MDM2 和 MDMX 蛋白提供了对 p53 肿瘤抑制因子的抑制作用，从而允许加速驱动癌症微进化的突变。MDM2/X-p53 相互作用的药理学阻断导致 p53 在 p53 细胞中重新激活，从而抑制癌症生长。在过去的 20 年中，已经提出了多种化学实体通过拮抗 MDM2/X 蛋白来重新激活 p53。
本文回顾了 2014-2018 年 MDM2/X 拮抗剂领域的治疗专利，是对类似主题的先前综述的延续。本文还介绍了涵盖 MDM2/X 拮抗剂在药物联合中的用途的专利，因为它们构成了 MDM2/X 拮抗剂在癌症治疗领域的一个重要趋势。
在 2014-2018 年期间，已经进一步开发和披露了几种以前已知的化学支架。重要的是，在同一时期，许多先导化合物已进入临床试验，用于治疗癌症患者。同时，有几项重要的报告指出了 MDM2 拮抗剂抗癌特性的严重局限性。因此，人们做出了许多努力来寻找联合抗癌治疗策略的积极协同治疗效果。最近的一个例子是利用 PROTAC 技术对 MDM2 和其他蛋白靶标进行双重靶向。
