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J Med Chem. 2018 Mar 22;61(6):2533-2551. doi: 10.1021/acs.jmedchem.7b01884. Epub 2018 Mar 7.

Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.

Author information

1
Sprint Bioscience AB, Novum , 14157 Huddinge , Sweden.
2
Bayer AG , Muellerstrasse 178 , 13353 Berlin , Germany.
3
Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , Oxford OX3 7DQ , United Kingdom.
4
Target Discovery Institute, Nuffield Department of Medicine , University of Oxford , Oxford OX3 7FZ , United Kingdom.

Abstract

Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.

PMID:
29485874
DOI:
10.1021/acs.jmedchem.7b01884
[Indexed for MEDLINE]

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