2. Academic Validation
  3. Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach

Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach

  • ACS Med Chem Lett. 2016 Jun 1;7(8):735-40. doi: 10.1021/acsmedchemlett.6b00167.
Chao Chen 1,  Hugh Zhu 1,  Frédéric Stauffer 2,  Giorgio Caravatti 2,  Susanne Vollmer 2,  Rainer Machauer 2,  Philipp Holzer 2,  Henrik Möbitz 2,  Clemens Scheufler 2,  Martin Klumpp 2,  Ralph Tiedt 2,  Kim S Beyer 2,  Keith Calkins 2,  Daniel Guthy 2,  Michael Kiffe 2,  Jeff Zhang 1,  Christoph Gaul 2
Affiliations

Affiliations

  • 1 Novartis Institutes for Biomedical Research , Shanghai 201203, China.
  • 2 Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
PMID: 27563395 DOI: 10.1021/acsmedchemlett.6b00167
Abstract

Oncogenic MLL fusion proteins aberrantly recruit DOT1L, a Histone Methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of DOT1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our DOT1L drug discovery program, high-throughput screening led to the identification of 2, a weak DOT1L Inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel DOT1L inhibitors.

Keywords

Dot1L; inhibitor; mixed lineage leukemia; protein lysine methyltransferase; protein structure-based design.

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