PMID- 32435413
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210514
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 11
IP  - 5
DP  - 2020 May 14
TI  - Structure-Guided Identification of DNMT3B Inhibitors.
PG  - 971-976
LID - 10.1021/acsmedchemlett.0c00011 [doi]
AB  - 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 muM 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 muM 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 muM. This result was well confirmed in an 
      ultrahigh-performance liquid chromatography (UHPLC)-based analytical assay, which 
      yielded an IC(50) of 4.8 muM. Structure-activity data are rationalized based on 
      computed structures for DNMT3B complexes.
CI  - Copyright (c) 2020 American Chemical Society.
FAU - Newton, Ana S
AU  - Newton AS
AD  - Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, 
      United States.
FAU - Faver, John C
AU  - Faver JC
AD  - Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, 
      United States.
FAU - Micevic, Goran
AU  - Micevic G
AD  - 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.
FAU - Muthusamy, Viswanathan
AU  - Muthusamy V
AD  - 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.
FAU - Kudalkar, Shalley N
AU  - Kudalkar SN
AD  - 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.
FAU - Bertoletti, Nicole
AU  - Bertoletti N
AD  - 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.
FAU - Anderson, Karen S
AU  - Anderson KS
AD  - 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.
FAU - Bosenberg, Marcus W
AU  - Bosenberg MW
AD  - 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.
AD  - 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.
AD  - 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.
FAU - Jorgensen, William L
AU  - Jorgensen WL
AD  - Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, 
      United States.
LA  - eng
GR  - R01 GM032136/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20200207
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC7236258
COIS- The authors declare no competing financial interest.
EDAT- 2020/05/22 06:00
MHDA- 2020/05/22 06:01
PMCR- 2021/05/14
CRDT- 2020/05/22 06:00
PHST- 2020/01/08 00:00 [received]
PHST- 2020/02/07 00:00 [accepted]
PHST- 2020/05/22 06:00 [entrez]
PHST- 2020/05/22 06:00 [pubmed]
PHST- 2020/05/22 06:01 [medline]
PHST- 2021/05/14 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.0c00011 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2020 Feb 7;11(5):971-976. doi: 10.1021/acsmedchemlett.0c00011. 
      eCollection 2020 May 14.