Synthesis and Characterization of Transition-State Analogue Inhibitors against Human DNA Methyltransferase 1

Farah Lamiable-Oulaidi, Rajesh K. Harijan, Karl J. Shaffer, Douglas R. Crump, Yan Sun, Quan Du, Shivali A. Gulab, Ashna A. Khan, Andreas Luxenburger, Anthony D. Woolhouse, Simone Sidoli, Peter C. Tyler, Vern L. Schramm

Research output: Contribution to journalArticlepeer-review

Abstract

Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S-adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S-adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.

Original languageEnglish (US)
Pages (from-to)5462-5494
Number of pages33
JournalJournal of Medicinal Chemistry
Volume65
Issue number7
DOIs
StatePublished - Apr 14 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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