Structure-Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI:10.1021/acsmedchemlett.4c00510

Jacob P Beard, Sierra L Love, John C Schmitz, Aaron A Hoskins, Kazunori Koide

引用次数: 0

Abstract

Meayamycins are synthetic analogs of the natural product FR901464 and exhibit potent anticancer activity against human cancers. They bind SF3B1 and PHF5A, components of the human spliceosome, and they alter pre-mRNA splicing. Detailed analysis of the active site led us to investigate a narrow pocket within the binding site that surrounds the α,β-unsaturated amide portion of meayamycin. We describe the synthesis and biological activity of two new analogs bearing a methyl substituent on the α or β position of the amide. With these analogs, we investigated the discrete interactions within the narrow region of SF3B1 using a human/yeast chimeric SF3B1 protein and found that the V1078 residue of SF3B1 affects compound binding at the amide moiety.

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Hsh155/SF3B1剪接调节剂的化学合成及酵母遗传学构效关系研究

meayamyins是天然产物FR901464的合成类似物，对人类癌症具有有效的抗癌活性。它们结合人类剪接体的组分SF3B1和PHF5A，并改变前mrna剪接。通过对活性位点的详细分析，我们发现了米亚霉素α，β-不饱和酰胺部分周围结合位点内的一个狭窄口袋。我们描述了在酰胺的α或β位置上具有甲基取代基的两个新的类似物的合成和生物活性。利用这些类似物，我们利用人/酵母嵌合的SF3B1蛋白研究了SF3B1狭窄区域内的离散相互作用，发现SF3B1的V1078残基影响酰胺部分的化合物结合。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.