Targeted control of function by chemical inducers of protein degradation of the histone methyltransferase KMT9 (CID-KMT9)

A. Vogelmann et al. Curr. Opin. Chem. Biol. 57 (2020) 8-16

Prof. Dr. Manfred Jung (CIBSS-AI), Institute of Pharmaceutical Sciences, Faculty of Chemistry and Pharmacy, University of Freiburg

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Prof. Dr. Roland Schüle (CIBSS-PI), Department of Urology and Centre for Clinical Research
University Medical Center Freiburg Faculty of Medicine

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional ligands simultaneously engaging a target of interest and an E3 ubiquitin ligase. This leads to target ubiquitinylation and proteosomal degradation. We identified and validated the histone methyltransferase KMT9 as novel regulator of epigenetic signalling, cellular metabolism and cancer cell proliferation and developed KMT9 inhibitors with sub nM potency and high selectivity. From this, we jointly realized the first PROTACs for KMT9 through structure-based design. Here we will optimize PROTACS for KMT9, analyze cellular events in KMT9 activation and downstream signalling and develop tools for site-specific PROTAC activation by enzymatic and light mediated uncaging.