Understanding spliceosome mechanism with small molecule inhibitors

The spliceosome is the cellular machinery responsible for removing introns from gene transcripts by the process of splicing, and a variety of cancers accumulate specific mutations that alter spliceosome activity. In particular, the spliceosome protein SF3B1, which helps identify the boundary of introns, is frequently mutated in hematologic cancers. Notably, SF3B1 is also the common target of several bacterial natural products that were first identified in screens for drugs that kill cancer cells. We are investigating the structure-activity relationships of three different classes of SF3B1 inhibitors. Some analogs that are inactive for splicing inhibition nevertheless compete with their active counterparts, which suggests that drug binding alone is not sufficient to interfere with splicing. Furthermore, the competition of inactive and active compounds holds between different classes of inhibitors, supporting shared pharmacophores. We are now using these compounds as tools to explore the role of SF3B1 in splice site identification and fidelity, as well as in structural transitions required for spliceosome assembly.












Melissa Jurica (UC Santa Cruz)