Structure-Guided Identification of DNMT3B Inhibitors.

Autor: Newton AS; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Faver JC; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Micevic G; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Muthusamy V; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Kudalkar SN; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Bertoletti N; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Anderson KS; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Bosenberg MW; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.; Department of Dermatology, Department of Medicine, Department of Pharmacology, Department of Pathology, and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Jorgensen WL; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Feb 07; Vol. 11 (5), pp. 971-976. Date of Electronic Publication: 2020 Feb 07 (Print Publication: 2020).
DOI: 10.1021/acsmedchemlett.0c00011
Abstrakt: 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.
Competing Interests: The authors declare no competing financial interest.
(Copyright © 2020 American Chemical Society.)
Databáze: MEDLINE
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