Mutations in several components of the spliceosome have been reported in various hematological (CLL, MDS, etc.) and solid tumor (melanoma, pancreatic, etc.) malignancies. SF3B1 is a component of the U2 snRNP complex of the spliceosome and is involved in the recognition of splice sites during early spliceosomal assembly. We and others have demonstrated that mutations in SF3B1 result in neomorphic activity and trigger the production of aberrantly spliced transcripts. Thus, the discovery of small molecule modulators of SF3B1 splicing activity may have therapeutic potential in cancers harboring SF3B1 mutations.<br/>Members of the pladienolide family of natural products have been shown to affect RNA splicing through modulation of the SF3b complex. While analogs of 6-deoxypladienolide D have been previously prepared via modification of the natural product, this semi-synthetic approach was particularly challenging due to the limited supply of 6-deoxypladienolide D and the synthetic inaccessibility to most regions of the molecule. For these reasons, coupled with the burgeoning interest to identify chemical matter able to modulate splicing in newly-identified mutant SF3B1 cancers, a total synthesis of 6-deoxypladienolide D using versatile and modular fragments was initiated.<br/>This presentation will describe the first total synthesis of the natural product 6-deoxypladienolide D. Two noteworthy attributes are: 1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and 2) the use of cost-effective starting materials and reagents to enable access to 6-deoxypladienolide D and its analogs for biological evaluation. In addition, we have found that 6-deoxypladienolide D demonstrates: 1) cellular lethality at single-digit nanomolar concentration in Panc 05.04 cells (a mutant SF3B1 cancer cell line), 2) high binding affinity to the SF3b complex, 3) ability to inhibit pre-mRNA splicing, and 4) modulation of aberrantly-spliced transcripts identified in mutant SF3B1 cells.

Total synthesis of 6-deoxypladienolide D and assessment of splicing inhibitory activity in a mutant SF3B1 cancer cell line

249th National Meeting (2015)

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