Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 an attractive therapeutic target. Here, we report the development of the first-in-class, potent and selective KMT9 inhibitor (compound 4, KMI169) through structure-based drug design. KMI169 functions as a bi-substrate inhibitor targeting the SAM and substrate binding pockets of KMT9 and exhibits high potency, selectivity, and cellular target engagement. KMT9 inhibition selectively downregulates target genes involved in transcription and cell cycle regulation and impairs proliferation of tumours cells including castration- and enzalutamide-resistant prostate cancer cells. Together, KMI169 represents a valuable tool to probe cellular KMT9 functions and paves the way for the development of clinical inhibitors as therapeutic options to treat malignancies such as therapy-resistant prostate cancer. Overall design: PC-3M prostate tumour cells were cultured 4 days in presence of DMSO, 360 nM of the KMT9 inhibitor KMI169, or 360 nM of the negative Ctrl compound KMI169 Ctrl prior to analyse the transcriptome.