Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.
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 of2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of2and3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of7, a highly potent, selective and structurally novel Dot1L inhibitor.
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Henrik
H
Möbitz
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Rainer
R
Machauer
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Philipp
P
Holzer
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Andrea
A
Vaupel
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Frédéric
F
Stauffer
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Christian
C
Ragot
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Giorgio
G
Caravatti
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Clemens
C
Scheufler
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Cesar
C
Fernandez
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Ulrich
U
Hommel
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Ralph
R
Tiedt
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Kim S
KS
Beyer
Novartis Institutes for Biomedical Research , Shanghai 201203, China.
Chao
C
Chen
Novartis Institutes for Biomedical Research , Shanghai 201203, China.
Hugh
H
Zhu
Novartis Institutes for Biomedical Research , 4002 Basel, Switzerland.
Christoph
C
Gaul
Dot1L; fragment linking; inhibitor; mixed lineage leukemia; protein lysine methyltransferase