Structure-Guided Identification of DNMT3B Inhibitors

Methyltransferase 3 beta (DNMT3B) inhibitors that interfere with cancer growth are emerging possibilities for treatment of melanoma. Herein we identify small molecule inhibitors of DNMT3B starting from a homology model based on a DNMT3A crystal structure. Virtual screening by docking led to purchase of 15 compounds, among which 5 were found to inhibit the activity of DNMT3B with IC values of 13-72 μM in a fluorogenic assay. Eight analogues of , , and were purchased to provide 2 more active compounds. Compound is particularly notable as it shows good selectivity with no inhibition of DNMT1 and 22 μM potency toward DNMT3B. Following additional design, exploratory synthesis of 17 analogues of delivered 5 additional inhibitors of DNMT3B with the most potent being with an IC of 8.0 μM. This result was well confirmed in an ultrahigh-performance liquid chromatography (UHPLC)-based analytical assay, which yielded an IC of 4.8 μM. Structure-activity data are rationalized based on computed structures for DNMT3B complexes.