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

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

  • ACS Med Chem Lett. 2024 Nov 25;15(12):2225-2230. doi: 10.1021/acsmedchemlett.4c00510.
Jacob P Beard 1,  Sierra L Love 2 3,  John C Schmitz 4 5,  Aaron A Hoskins 2 6,  Kazunori Koide 1 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
  • 2 Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706, United States.
  • 3 Genetics Training Program, University of Wisconsin-Madison, 425 Henry Mall, Madison, Wisconsin 53706, United States.
  • 4 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15232, United States.
  • 5 Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, Pennsylvania 15232, United States.
  • 6 Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
PMID: 39691513 DOI: 10.1021/acsmedchemlett.4c00510
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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