title: Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.
abstract: Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.
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: Henrik
authors: H
authors: Möbitz
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Christoph
authors: C
authors: Gaul
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Christian
authors: C
authors: Ragot
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Céline
authors: C
authors: Be
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: César
authors: C
authors: Fernández
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: Ralph
authors: R
authors: Tiedt
authors: Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
authors: Frédéric
authors: F
authors: Stauffer
keywords: Dot1L; fragment-based screen; inhibitor; lysine histone methyltransferase; structure-based design