Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 5, Pages 971-976Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00011
Keywords
DNMT3B; DNMT3A; DNMT1; melanoma; virtual screening; structure-based drug design
Categories
Funding
- National Institutes of Health [GM32136]
- Melanoma Research Alliance
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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 mu M in a fluorogenic assay. Eight analogues of 7, 10, and 12 were purchased to provide 2 more active compounds. Compound 11 is particularly notable as it shows good selectivity with no inhibition of DNMT1 and 22 mu M potency toward DNMT3B. Following additional de novo design, exploratory synthesis of 17 analogues of 11 delivered 5 additional inhibitors of DNMT3B with the most potent being 33h with an IC50 of 8.0 mu M. This result was well confirmed in an ultrahigh-performance liquid chromatography (UHPLC)-based analytical assay, which yielded an IC50 of 4.8 mu M. Structure-activity data are rationalized based on computed structures for DNMT3B complexes.
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