A Comprehensive Overview of Structure‐Activity Relationships of Small‐Molecule Splicing Modulators Targeting SF3B1 as Anticancer Agents,ChemMedChem

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A Comprehensive Overview of Structure‐Activity Relationships of Small‐Molecule Splicing Modulators Targeting SF3B1 as Anticancer Agents
ChemMedChem ( IF 3.6 ) Pub Date : 2020-10-09 , DOI: 10.1002/cmdc.202000642
Datong Zhang ₁ , Fancui Meng ₂

Affiliation

The pre‐mRNA splicing factor SF3B1 shows recurrent mutations among hematologic malignancies and some solid tumors. In 2007, the identification of two cytotoxic natural products, which showed splicing inhibition by binding to SF3b, prompted the development of small‐molecule splicing modulators of SF3B1 as therapeutics for cancer. Recent studies suggested that spliceosome‐mutant cells are preferentially sensitive to pharmacologic splicing modulation; therefore, exploring the clinical utility of splicing modulator therapies in patients with spliceosome‐mutant hematologic malignancies who have failed current therapies is greatly needed, as these patients have few treatment options. H3B‐8800 had unique pharmacological activity and exhibited favorable data in phase I clinical trials to treat patients with advanced myeloid malignancies, indicating that further clinical trials are promising. The most established small‐molecule modulators of SF3B1 can be categorized into three classes: the bicycles, the monopyranes, and the 12‐membered macrolides. This review provides a comprehensive overview of the structure‐activity relationships of small‐molecule SF3B1 modulators, with a detailed analysis of interactions between modulators and protein binding pocket. The future strategy for splicing modulators development is also discussed.

中文翻译：

靶向 SF3B1 作为抗癌剂的小分子剪接调节剂的构效关系综合概述

前体 mRNA 剪接因子 SF3B1 在血液系统恶性肿瘤和一些实体瘤中显示出复发性突变。2007 年，鉴定出两种通过与 SF3b 结合抑制剪接的细胞毒性天然产物，促进了 SF3B1 小分子剪接调节剂作为癌症治疗剂的开发。最近的研究表明，剪接体突变细胞对药理剪接调节优先敏感。因此，非常需要探索剪接调节剂疗法在当前疗法失败的剪接体突变血液系统恶性肿瘤患者中的临床效用，因为这些患者几乎没有治疗选择。H3B-8800 具有独特的药理活性，在治疗晚期髓系恶性肿瘤患者的 I 期临床试验中显示出有利的数据，表明进一步的临床试验很有希望。SF3B1 最成熟的小分子调节剂可分为三类：自行车、单吡喃和 12 元大环内酯。本综述全面概述了小分子 SF3B1 调节剂的构效关系，并详细分析了调节剂与蛋白质结合口袋之间的相互作用。还讨论了剪接调节剂开发的未来策略。详细分析了调节剂和蛋白质结合口袋之间的相互作用。还讨论了剪接调节剂开发的未来策略。详细分析了调节剂和蛋白质结合口袋之间的相互作用。还讨论了剪接调节剂开发的未来策略。

更新日期：2020-11-18

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