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

ChemMedChem, ISSN: 1860-7187, Vol: 15, Issue: 22, Page: 2098-2120
2020
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Review Description

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.

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