Targeting Protein-Protein Interactions for Disruption of LSD1 (KDM1A) Complexes
Jennifer Link Schwabe, Ph.D. candidate
Dewey McCafferty, advisor
Friday, March 24, 2017 -
9:30am to 10:30am
Location: French Family Science Center 1243
Avery, Meg

Lysine-specific demethylase 1 (LSD1/KDM1A) is a histone demethylase implicated widely in both normal cell function and disease. The recent development of highly-selective LSD1 inhibitors has further highlighted its importance in acute myeloid leukemia and small cell lung carcinoma. Using these tools, we have demonstrated that chemical inhibition of LSD1 has little effect on breast cancer cell proliferation, while knockdown by siRNA drastically reduces growth rate. This suggests that LSD1 performs critical functions independent of its demethylation activity. To further probe this dichotomy, we characterized the binding interaction between LSD1 and its partner protein CoREST. The interface between these proteins contains a region of localized binding energy that is likely critical for LSD1 stabilization. We furthermore used this interaction as a template for design of a first-generation probe, which we demonstrate is capable of competing with endogenous LSD1 interactions and disrupting estrogen signaling in a model of breast cancer. We believe these protein-protein interaction inhibitors show great promise for the selective inhibition of specific protein functions.