Open AccessStructure-Guided Identification of DNMT3B Inhibitors
Author(s) -
Ana S. Newton,
John C. Faver,
Goran Micevic,
Viswanathan Muthusamy,
Shalley N. Kudalkar,
Nicole Bertoletti,
Karen S. Anderson,
Marcus W. Bosenberg,
William Jorgensen
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00011
Subject(s) - virtual screening , chemistry , ic50 , small molecule , methyltransferase , dnmt3b , homology modeling , docking (animal) , combinatorial chemistry , potency , stereochemistry , computational biology , pharmacology , enzyme , biochemistry , in vitro , pharmacophore , medicine , biology , methylation , nursing , gene
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 50 values of 13-72 μM 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 μM 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 IC 50 of 8.0 μM. This result was well confirmed in an ultrahigh-performance liquid chromatography (UHPLC)-based analytical assay, which yielded an IC 50 of 4.8 μM. Structure-activity data are rationalized based on computed structures for DNMT3B complexes.