Structure-Guided Identification of DNMT3B Inhibitors
| Autor: | William L. Jorgensen, Karen S. Anderson, Marcus Bosenberg, Nicole Bertoletti, John C. Faver, Shalley N. Kudalkar, Ana S. Newton, Goran Micevic, Viswanathan Muthusamy |
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| Rok vydání: | 2020 |
| Předmět: |
Virtual screening
Methyltransferase 010405 organic chemistry Chemistry Organic Chemistry 01 natural sciences Biochemistry Small molecule Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Docking (molecular) embryonic structures Drug Discovery Potency Homology modeling Selectivity IC50 |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00011 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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