TY - JOUR
T1 - Synthesis and Characterization of Transition-State Analogue Inhibitors against Human DNA Methyltransferase 1
AU - Lamiable-Oulaidi, Farah
AU - Harijan, Rajesh K.
AU - Shaffer, Karl J.
AU - Crump, Douglas R.
AU - Sun, Yan
AU - Du, Quan
AU - Gulab, Shivali A.
AU - Khan, Ashna A.
AU - Luxenburger, Andreas
AU - Woolhouse, Anthony D.
AU - Sidoli, Simone
AU - Tyler, Peter C.
AU - Schramm, Vern L.
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/14
Y1 - 2022/4/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.1c01869
DO - 10.1021/acs.jmedchem.1c01869
M3 - Article
C2 - 35324190
AN - SCOPUS:85127592042
SN - 0022-2623
VL - 65
SP - 5462
EP - 5494
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -