Beard Jacob P, Love Sierra L, Schmitz John C, Hoskins Aaron A, Koide Kazunori
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706, United States.
ACS Med Chem Lett. 2024 Nov 25;15(12):2225-2230. doi: 10.1021/acsmedchemlett.4c00510. eCollection 2024 Dec 12.
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.
米阿霉素是天然产物FR901464的合成类似物，对人类癌症具有强大的抗癌活性。它们结合人剪接体的组分SF3B1和PHF5A，并改变前体mRNA剪接。对活性位点的详细分析使我们研究了结合位点内围绕米阿霉素α,β-不饱和酰胺部分的一个狭窄口袋。我们描述了两种在酰胺的α或β位带有甲基取代基的新类似物的合成及生物活性。利用人/酵母嵌合SF3B1蛋白，我们用这些类似物研究了SF3B1狭窄区域内的离散相互作用，发现SF3B1的V1078残基影响化合物在酰胺部分的结合。
