Structure-activity relationship study of splicing modulators on Hsh155/SF3B1 through chemical synthesis and yeast genetics

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 alter pre-mRNA splicing. Detailed analysis of the active site led us to investigate a narrow pocket within the binding site which surrounds the ,-unsaturated amide portion of meayamycin. We describe the synthesis and biological activity of two new analogs bearing a methyl substituent on the or 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 the V1078 residue of SF3B1 affects compound binding at the amide moiety.