Targeting the spliceosome with small molecule inhibitors offers an opportunity to target alternate mRNA splicing pathways for therapeutic applications. Although our understanding of alternate mRNA splicing remains poorly understood, it provides an escape pathway for many cancers resistant to current therapeutics. We describe the application of semi-synthesis and total synthesis to reveal key structure activity relationships for FD-895 spliceosome inhibition and the applicaiton of this information to deliver new analogs with improved stability and potent activity at inhibiting splicing in patient-derived cell lines.

Stabilized cyclopropane analogs of the spliceosome Inhibitor FD-895

249th National Meeting (2015)

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