title: Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.
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.
authors: Novartis Institutes for Biomedical Research , Shanghai 201203, China.
authors: Chao
authors: C
authors: Chen
authors: Novartis Institutes for Biomedical Research , Shanghai 201203, China.
authors: Hugh
authors: H
authors: Zhu
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Frédéric
authors: F
authors: Stauffer
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Giorgio
authors: G
authors: Caravatti
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Susanne
authors: S
authors: Vollmer
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Rainer
authors: R
authors: Machauer
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Philipp
authors: P
authors: Holzer
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Henrik
authors: H
authors: Möbitz
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Clemens
authors: C
authors: Scheufler
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Martin
authors: M
authors: Klumpp
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Ralph
authors: R
authors: Tiedt
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Kim S
authors: KS
authors: Beyer
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Keith
authors: K
authors: Calkins
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Daniel
authors: D
authors: Guthy
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Michael
authors: M
authors: Kiffe
authors: Novartis Institutes for Biomedical Research , Shanghai 201203, China.
authors: Jeff
authors: J
authors: Zhang
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Christoph
authors: C
authors: Gaul
keywords: Dot1L; inhibitor; mixed lineage leukemia; protein lysine methyltransferase; protein structure-based design