Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach

  • ACS Med Chem Lett. 2017 Feb 14;8(3):338-343. doi: 10.1021/acsmedchemlett.6b00519.
Henrik Möbitz  1 ,  Rainer Machauer  1 ,  Philipp Holzer  1 ,  Andrea Vaupel  1 ,  Frédéric Stauffer  1 ,  Christian Ragot  1 ,  Giorgio Caravatti  1 ,  Clemens Scheufler  1 ,  Cesar Fernandez  1 ,  Ulrich Hommel  1 ,  Ralph Tiedt  1 ,  Kim S Beyer  1 ,  Chao Chen  2 ,  Hugh Zhu  2 ,  Christoph Gaul  1
Affiliations
  • 1. Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
  • 2. Novartis Institutes for Biomedical Research , Shanghai 201203, China.
PMID: 28337327 DOI: 10.1021/acsmedchemlett.6b00519
Abstract

Misdirected catalytic activity of Histone Methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of DOT1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive DOT1L hit finding strategy, a knowledge-based virtual screen of the DOT1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to DOT1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel DOT1L Inhibitor.

Keywords
Dot1L; fragment linking; inhibitor; mixed lineage leukemia; protein lysine methyltransferase.
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