Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.).
Pharmacol Rev. 2024 May 2;76(3):414-453. doi: 10.1124/pharmrev.123.001026.
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. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.
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 的活性从致癌作用到免疫反应到对各种癌症治疗的反应都有涉及。自从 30 多年前报道了第一个 MDM2 抑制剂以来，已经尝试了各种抑制 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。尽管已经在临床试验中评估了许多 MDM2 抑制剂和降解剂，但目前市场上没有获得美国食品和药物管理局 (FDA) 批准的 MDM2 抑制剂。然而，目前有几个有前途的药物的临床试验，这些药物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。本文总结了发现和开发 MDM2 抑制剂的研究工作，重点介绍了那些诱导 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朝着将 MDM2 抑制剂与其他药物（包括免疫检查点抑制剂）联合使用的方向发展。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 仍然是一种很有前途的治疗方法，靶向 MDM2 进行蛋白降解代表了一种下调 MDM2 的新策略，而不会产生现有药物阻断 p53-MDM2 结合的副作用。需要进行更多的临床前和临床研究，以充分发挥 MDM2 抑制在治疗癌症和其他涉及 MDM2 的慢性疾病中的潜力。
MDM2 癌基因的过表达/扩增已在各种人类癌症中检测到，并与疾病进展、治疗耐药性和患者预后不良有关。本文综述了以前、当前和新兴的 MDM2 靶向治疗方法，并总结了将 MDM2 抑制剂与化疗和免疫治疗方案联合使用的临床前和临床研究。这些当代研究的发现可能为过表达 MDM2 的癌症患者提供更安全、更有效的治疗方法。
Zotero 插件
