Next Generation Splice Modulators: Potentially Powerful Tumor Suppressors

Undergraduate #26
Discipline: Chemistry and Chemical Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)

Terrance J. Haanen III - California State University, San Marcos

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Splicing events have been shown to have a correlation with disease onset. Small molecule splice modulators (SPLMs) can intercept alternative splicing pathways. Natural product SPLMs have been shown to have splice inhibiting activity and are cytotoxic when tested with the HCT-116 cancer cell line. These SPLMs such as FD-895, however, have an unstable cyclic structure and a side chain. Next generation SPLMs must have increased stability when exposed to nucleophilic environments, pH change, and enzyme activity. A cyclopropane analog was synthesized, able to mimic the splicing activity of the original natural product, and was shown to be cytotoxic. The improved stability shows there is room for more development. These new class of SPLMs are more stable and prevent off-target responses that are common with previous SPLMs. Our goal is to identify SPLMs with greater stability and enhanced pharmacological properties. The carbohydrate motif provides a better scaffold than the previous generation of SPLMs, as many sugars are readily available and can be easily modified. Carbohydrate-based splice modulators have considerable potential for therapeutic applications for a wide range of solid cancers.

Funder Acknowledgement(s): National Institutes of Health; University of California, San Diego STARS Program

Faculty Advisor: Michael Burkart, mburkart@ucsd.edu

Role: The extent of my work on this research project included performing various organic chemistry reactions that were necessary to synthesize the various analog's that would later be tested to determine their efficacy in preventing tumorigenesis in a human tissue sample containing colon cancer. The analog's efficacy was tested using an MTT assay which provided a relative percentage of live cells after the cell line was inoculated for 72 hours.