Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96_MDM2. The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐c]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects.

中文翻译：

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偶氮基叶立德分子的分子内环化靶向合成复杂的螺[3H-吲哚-3,2'-吡咯烷基] -2（1H）-ones：强效MDM2-p53抑制剂

小鼠双分钟2（MDM2）是重要的肿瘤抑制因子p53的主要直接抑制剂。初步临床试验的报告表明，用小分子抑制剂阻断这种相互作用在p53野生型肿瘤患者的癌症治疗中具有重要价值。但是，它也揭示了限制剂量的血液学毒性和药物诱导的耐药性是主要问题。为了克服前者，需要一种具有出色效价和药代动力学特性的抑制剂，以便最终以较少的给药时间表最终获得全部功效。为了实现这一目标，我们通过重点研究与His96 _MDM2氨基酸侧链的关键相互作用，优化了我们最近报道的螺-羟吲哚抑制剂。。设计的分子需要靶向合成结构复杂的螺[吲哚-3,2'-吡咯并[2,3- c ]吡咯] -2,4'-二酮，为此我们开发了空前的分子内甲亚胺叶立德环加成并研究了结果通过计算方法。一种新化合物显示出比以前报道的BI-0252更高的细胞效力。这一发现是朝着减轻潜在血液学目标不良影响的抑制剂迈出的重要一步。