Project Grant R43CA287469

SYNTHETIC BIOLOGY FOR SPLICE MODULATING POLYKETIDES - PROJECT SUMMARY. NATURAL PRODUCT-DERIVED RNA SPLICE MODULATORS ARE BEING DEVELOPED FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA AS WELL AS OTHER CANCERS. AS NATURAL PRODUCTS WITH COMPLEX MOLECULAR ARCHITECTURES, ANALOGUE SYNTHESIS, EVALUATION, AND PRODUCTION SCALE UP HAVE PROVEN CHALLENGING. HERE WE UTILIZE THE TOOLS OF SYNTHETIC BIOLOGY AS A PLATFORM TO SYNTHESIZE COMPLEX POLYKETIDE SPLICE MODULATORS. THE MOST ESTABLISHED SET OF SPLICE MODULATORS SHARE A COMMON MODE OF ACTION TARGETING THE SF3B MULTI-PROTEIN COMPONENT WITHIN THE U2- SNRNP OF THE SPLICEOSOME. THEY ALSO SHARE A COMMON MOTIF COMPRISED OF TWO FUNCTIONAL MOIETIES UNITED THROUGH A CENTRAL DIENE. COMBINING THE MOLECULAR DIVERSITY PROVIDED BY MEDICINAL CHEMISTRY WITH THE FLEXIBILITY AND THE ABILITY TO SCALE METABOLITE PRODUCTION USING SYNTHETIC BIOLOGY, WE WILL PRODUCE 17S-FD-895, A HIGHLY POTENT, IN VIVO ACTIVE LEAD FOR AML. THIS WILL OVERCOME THE CHEMICAL PRODUCTION BOTTLENECK THAT IS PREVENTING THIS LIFE SAVING COMPOUND FROM REACHING CLINICAL TRIALS. FROM THIS MEDICINAL SYNTHETIC BIOLOGY APPROACH, WE WILL IDENTIFY A PROMISING PRODUCTION CANDIDATE THAT HAS THE PRE-CLINICAL CREDENTIALS TO BE FURTHER DEVELOPED AS A NOVEL ANTICANCER THERAPEUTIC.