Synthesis of Selective Inhibitors of Histone Methyltransferases as Potential Anti

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DESCRIPTION (provided by applicant): In this proposal, I discuss the importance of histone methyltransferases (HMTs), specifically SUV39H1, and their role in the treatment of cancer. The long-term goal of the project is to develop SUV39H1 inhibitors that could potentially be used for cancer chemotherapy. The normal function of SUV39H1 is to trimethylate lysine 9 of histone 3 (H3K9) but is overexpressed in some cancers. Trimethylation of H3K9 in cancer cells is detected at promoter regions of tumor suppressor genes, making inhibition of SUV39H1 a possible strategy for cancer chemotherapy. Dr. Larry Overman and co-workers have synthesized a compound, LEO-12-1406, with an epidithiodiketopiperazine (ETP) scaffold that is a potent and highly selective inhibitor of SUV39H1. Currently the binding mode of this ETP compound with the HMT is unknown. One of professor Overman's collaborators, Dr. John Williams (Beckman Research Institute, City of Hope) has cloned SUV39H1 and is attempting crystallization with ETP analogs such as LEO-12-1406 bound. Until this X-ray data is available, we are relying on docked homology models of SUV39H1 and LEO-12-1406 constructed by another collaborator of Professor Overman's (Professor David Mobley, UCI Department of Pharmaceutical Sciences) to predict possible binding sites. Using these models, I have posited four hypotheses of binding. I will prepare several ETP analogs that upon biological evaluation will indicate whether these assertions are accurate. With the exception of two compounds, the synthesis of LEO-12-1406 analogs will be accomplished by a five step sequence. The other objective of this proposal is the synthesis of glionitrin A, an ETP natural product that would allo us to explore another scaffold for HMT inhibition. The total synthesis as outlined would be accomplished in less than 10 steps. The development of a potent SUV39H1 inhibitor could potentially improve the treatment of some cancer types and improve outlook for patients. Similarly, the synthesis of glionitrin A would allow access to analogs with a different scaffold than the currently proposed ETP analogs.