The long-term goal of our research is to build a mechanistic model of spliceosome function. The spliceosome catalyzes pre-mRNA splicing, which is a crucial step in eukaryotic gene expression, and abnormal splicing underlies many human diseases, including cancers. Understanding this critical cellular machine in normal, healthy situations is the necessary first step to determining how aberrant changes in spliceosome activity is linked to cancer. The spliceosome consists of over 100 proteins, and we lack mechanistic information for the vast majority of them. One of the core spliceosome proteins is SF3B1, which is frequently mutated in several different types of cancer. SF3B1 is also the target of natural anti-tumor products. Our objectives are to determine the role of the spliceosome core protein SF3B1 in the spliceosome assembly process and to determine the structure activity relationships of SF3B1 inhibitors. We will achieve these goals using an in vitro splicing system to characterize the effect of synthetic inhibitor analogs. Our research on SF3B1 is significant because deciphering the function of a core spliceosome protein will fill a large gap in our mechanistic understanding of the splicing process. Furthermore, understanding the role of SF3B1 promises to impact active research efforts to uncover the dependence of cancer cells on splicing, and to inform the development of new chemotherapeutics based on splicing modulation.
In humans, normal, healthy gene expression is dependent upon a complex macromolecular machine called the spliceosome. Compellingly, components of the spliceosome are mutated in a variety of cancers including leukemia and breast cancer. We aim to determine how spliceosome components function in splicing and how inhibitors affect their activity, which is necessary to understanding how changes in the spliceosome contribute to cancer development, and eventually creating new anti-tumor drugs that target spliceosomes.
| Ghosh, Arun K; Veitschegger, Anne M; Nie, Shenyou et al. (2018) Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition. J Org Chem 83:5187-5198 |
| Ghosh, Arun K; Reddy, Guddeti Chandrashekar; MacRae, Andrew J et al. (2018) Enantioselective Synthesis of Spliceostatin G and Evaluation of Bioactivity of Spliceostatin G and Its Methyl Ester. Org Lett 20:96-99 |
