Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive types of cancer and is extremely challenging to treat. The sirtuin 6 protein (SIRT6), a multifunctional enzyme involved in gene regulation, was found to be associated with PDAC oncogenesis. SIRT6 inactivation induces overproduction of a miRNA-binding protein, Lin28b, which subsequently impedes the maturation of the tumor suppressor miRNA, Let-7, through increased binding to its precursor. Inhibition of this pathway provides an attractive target for novel PDAC therapies. Previous research has resolved the crystal structure of the protein:miRNA complex and identified, in vitro, small molecule inhibitors of the binding interface. Drawing from these studies, a dual approach is presented, involving virtual high-throughput screening (vHTS) and de novo drug design, to identify novel potential inhibitors. Selected targets are purchased if commercially available or synthesized in our laboratory. An in vitro assay is concurrently being developed to validate the targets’ abilities to competitively inhibit Lin28b binding to the Let-7 precursor. It is anticipated that successful inhibitors will be evaluated in human PDAC cells.

Identification, validation, and synthesis of small molecule inhibitors of the Lin28b/pre-Let-7 interaction in pancreatic ductal adenocarcinoma

2019 Spring National Meeting

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