Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated.

中文翻译：

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MDM2 抑制剂用于癌症治疗：过去、现在和未来

自 35 年前发现以来，MDM2 已成为癌症治疗开发的一个有吸引力的靶点。 MDM2 的活性从致癌作用延伸到免疫，再到对各种癌症治疗的反应。自从 30 多年前第一个 MDM2 抑制剂被报道以来，人们尝试了各种抑制 MDM2 的方法，在临床前研究中评估了数百种小分子抑制剂，并在临床试验中测试了许多分子。尽管许多MDM2抑制剂和降解剂已经在临床试验中进行了评估，但目前市场上还没有美国食品和药物管理局（FDA）批准的MDM2抑制剂。尽管如此，目前有一些有前途的药物的临床试验可能会克服过去的失败，包括获得 FDA 孤儿药或快速通道地位的药物。我们在此总结了发现和开发 MDM2 抑制剂的研究工作，重点关注那些诱导 MDM2 降解并发挥抗癌活性的抑制剂，无论癌症的 p53 状态如何。我们还描述了临床前和临床研究如何将 MDM2 抑制剂与其他药物（包括免疫检查点抑制剂）相结合。最后，我们讨论了加速MDM2抑制剂临床应用的当前挑战和未来方向。总之，靶向 MDM2 仍然是一种有前途的治疗方法，并且靶向 MDM2 进行蛋白质降解代表了一种下调 MDM2 的新策略，且不会产生阻断 p53-MDM2 结合的现有药物的副作用。需要进行更多的临床前和临床研究，以最终实现 MDM2 抑制在治疗癌症和其他涉及 MDM2 的慢性疾病方面的全部潜力。