Human SET domain bifurcated 1 (SETDB1), Tudor domain; A Target Enabling Package

SETDB1 is a H3K9 methyltransferase involved in transcriptional silencing with a catalytic SET domain and a triple Tudor domain containing a methyl-lysine binding site. SGC Toronto previously solved the apo structure of the Tudor domain (PDB code 3DLM). Amplification of SETDB1 in over 15% lung adenocarcinoma correlates with high mRNA and protein levels and its depletion in SETDB1-amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases tumour invasiveness (Rodriguez-Paredes et al. Oncogene 2014, Shah et al. Epigenetic Chromatin 2014). Several histone methyltransferases are known to have non-catalytic functions that might be alternative targeting strategies. For instance, recognition of H3K9 methylation by the ankyrin repeat of the methyltransferase GLP is required for efficient establishment of H3K9 methylation (Liu et al. Genes Dev. 2015). No catalytic domain inhibitor of SETDB1 has been reported to date. The goal of this TEP is to enable the discovery of potent, selective compounds targeting the Tudor domain of SETDB1.