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Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

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.

SUBMITTER: Mobitz H

PROVIDER: S-EPMC5346981 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

Möbitz Henrik H Machauer Rainer R Holzer Philipp P Vaupel Andrea A Stauffer Frédéric F Ragot Christian C Caravatti Giorgio G Scheufler Clemens C Fernandez Cesar C Hommel Ulrich U Tiedt Ralph R Beyer Kim S KS Chen Chao C Zhu Hugh H Gaul Christoph C

ACS medicinal chemistry letters 20170214 3

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 <b>2</b>, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment link ...[more]

PMID: 28337327

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