Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L

  • Medchemcomm. 2013 May 1;4(5):822-826. doi: 10.1039/C3MD00021D.
Lisheng Deng  1 ,  Li Zhang ,  Yuan Yao ,  Cong Wang ,  Michele S Redell ,  Shuo Dong ,  Yongcheng Song
Affiliations
  • 1. Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States. ; Tel: +1 713-798-7415.
PMID: 23795283 DOI: 10.1039/C3MD00021D
Abstract

Histone Methyltransferase DOT1L is a drug target for MLL leukemia. We report an efficient synthesis of a cyclopentane-containing compound that potently and selectively inhibits DOT1L (Ki = 1.1 nM) as well as H3K79 methylation (IC50 ~ 200 nM). Importantly, this compound exhibits a high stability in plasma and liver microsomes, suggesting it is a better drug candidate.