Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.
ACS Med Chem Lett
; 8(3): 338-343, 2017 Mar 09.
Article
in En
| MEDLINE
| ID: mdl-28337327
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
ACS Med Chem Lett
Year:
2017
Document type:
Article
Affiliation country:
Switzerland