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Targeting the Spliceosome through Novel Inhibitors as Therapeutic Approaches to AML and CLL

Warren Chan
Appointment Period: 2017-2018, Grant Year: [31, 32]

Warren Chan

Finding new therapeutic routes to fight cancer-related diseases remains one of the tallest hurdles in human health. Recently, a flurry of publications has identified the spliceosome, the huge macromolecular assembly comprised of five small nuclear ribosomal proteins (snRNP) that catalyzes the splicing of all eukaryotic genes, as a promising target for anti-cancer therapeutics.

The majority of known spliceosome inhibitors target a subunit important in maintaining fidelity called splicing factor 3 subunit 1 (SF3B1). In a number of diseases and cancers, specifically acute myeloid and chronic lymphocytic leukemia, a mutation in SF3B1 results in differential splicing of genes that regulate tumor suppression and allow for up-regulation of anti- apoptotic pathways. Over the past decade, the Burkart Lab has developed synthetic methodologies to access a potent spliceosome inhibitor, FD-895, and is the first in its class to show specificity towards leukemia cells in the presence of healthy white blood cells. Although it exhibits low nanomolar activity, its structural complexity prevents access to large quantities of material needed for clinical trials.

My research is two-fold: 1.) To apply a medicinal chemical approach to interrogate the minimal and necessary functionalities of FD-895 that maintain its activity. 2.) To employ structural activity relationships developed above to design a more potent and synthetically feasible analog of FD-895.

PUBLICATIONS (resulting from this training)

León B, Kashyap MK, Chan WC, Krug KA, Castro JE, La Clair JJ, Burkart MD. A Challenging Pie to Splice: Drugging the Spliceosome. (2017) Angew Chem Int Ed Engl. 56(40): 12052-12063. PMID: 28371109

León B, Chan WC, Patel A, Krug KA, Ndukwe I, Martin GE, Williamson T, Villa R, Jaremko MJ, McCammon JA, La Clair, JJ, Burkart MD. A Structural Elucidation of Splice Modulation via SF3B. In preparation.