Structure-Guided Identification of DNMT3B Inhibitors

Abstract

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 IC₅₀ values of 13-72 μM in a fluorogenic assay. Eight analogues of <b>7</b>, <b>10</b>, and <b>12</b> were purchased to provide 2 more active compounds. Compound <b>11</b> is particularly notable as it shows good selectivity with no inhibition of DNMT1 and 22 μM potency toward DNMT3B. Following additional <i>de novo</i> design, exploratory synthesis of 17 analogues of <b>11</b> delivered 5 additional inhibitors of DNMT3B with the most potent being <b>33h</b> with an IC₅₀ of 8.0 μM. This result was well confirmed in an ultrahigh-performance liquid chromatography (UHPLC)-based analytical assay, which yielded an IC₅₀ of 4.8 μM. Structure-activity data are rationalized based on computed structures for DNMT3B complexes.