Analogues of the Natural Product Sinefungin as Inhibitors of EHMT1 and EHMT2

Kanchan Devkota; Brian Lohse; Qing Liu; Ming-Wei Wang; Dan Stærk; Jens Berthelsen; Rasmus Prætorius Clausen

doi:10.1021/ml4002503

Analogues of the Natural Product Sinefungin as Inhibitors of EHMT1 and EHMT2

ACS Med Chem Lett. 2014 Jan 31;5(4):293-7. doi: 10.1021/ml4002503. eCollection 2014 Apr 10.

Authors

Kanchan Devkota¹, Brian Lohse², Qing Liu³, Ming-Wei Wang³, Dan Stærk², Jens Berthelsen⁴, Rasmus Prætorius Clausen²

Affiliations

¹ The NNF Center for Protein Research, University of Copenhagen , Blegdamsvej 3B, DK-2200 Copenhagen, Denmark ; Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
² Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
³ The National Center for Drug Screening and the Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
⁴ The NNF Center for Protein Research, University of Copenhagen , Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.

Abstract

A series of analogues of the natural product sinefungin lacking the amino acid moiety was synthesized and probed for their ability to inhibit EHMT1 and EHMT2. This study led to inhibitors 3b and 4d of methyltransferase activity of EHMT1 and EHMT2 and it demonstrates that such analogues constitute an interesting scaffold to develop selective methyltransferase inhibitors. Surprisingly, the inhibition was not competitive toward AdoMet.

Keywords: EHMT1; EHMT2; Sinefungin; methyltransferase inhibitors.