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

Journal of Medicinal Chemistry
Fredrik RahmMartin Andersson

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.

References

Apr 19, 1994·Biochemistry·Y I PavlovT A Kunkel
Oct 11, 1996·The Journal of Biological Chemistry·M J BessmanS F O'Handley
Feb 13, 2002·Current Opinion in Structural Biology·Warren L DeLano
May 31, 2002·Acta Crystallographica. Section D, Biological Crystallography·Helen M BermanChristine Zardecki
Dec 14, 2002·Journal of Molecular Graphics & Modelling·Susanne WiniwarterAnders Karlén
Apr 28, 2004·Drug Discovery Today·Andrew L HopkinsAlexander Alex
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Jul 26, 2006·Free Radical Biology & Medicine·Siamak HaghdoostMats Harms-Ringdahl
Aug 4, 2006·Journal of Medicinal Chemistry·Alessio CiulliChris Abell
Sep 25, 2007·Chemistry & Biodiversity·Bernard Testa, Stefanie D Krämer
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Oct 16, 2009·Journal of Medicinal Chemistry·Frank LoveringChristine Humblet
Dec 19, 2009·Toxicologic Pathology·James E KlaunigBarbara A Hocevar
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 8, 2010·Free Radical Research·Geou-Yarh Liou, Peter Storz
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jan 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Lingle WangR A Friesner
Feb 15, 2011·Drug Discovery Today·Fredrik N B EdfeldtAlexander L Breeze
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Jul 27, 2011·FEBS Letters·Linda M SvenssonPål Stenmark
May 1, 2012·Nature Reviews. Drug Discovery·Michael M Hann, György M Keserü
Nov 30, 2013·Nature Reviews. Drug Discovery·Chiara GorriniTak W Mak
Jan 25, 2014·Journal of Chemical Information and Modeling·Katarina RoosMats Svensson
Apr 4, 2014·Nature·Kilian V M HuberGiulio Superti-Furga
Dec 3, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jean-Yves MérourSylvain Routier
Jul 21, 2015·ACS Medicinal Chemistry Letters·Paul D Leeson, Robert J Young
Jul 22, 2015·Nature Chemical Biology·Cheryl H ArrowsmithWilliam J Zuercher
Feb 18, 2016·Journal of Medicinal Chemistry·Jason G KettleMarta Wylot
Feb 24, 2016·Bioorganic & Medicinal Chemistry Letters·Alessia PetrocchiRichard T Lewis
Mar 22, 2016·PloS One·J Willem M NissinkJon J Winter-Holt
Jan 16, 2017·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Jong Bong LeePavel Gershkovich
May 10, 2017·Cancers·Govindi J SamaranayakePriyamvada Rai
May 20, 2017·Nature Reviews. Cancer·William G Kaelin
Jul 6, 2017·ACS Chemical Biology·Manuel EllermannMátyás Gorjánácz
Jul 12, 2017·Cancer Cell·Julian Blagg, Paul Workman
Sep 21, 2017·Journal of Medicinal Chemistry·Axel RudlingJens Carlsson

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Citations

Mar 23, 2021·ACS Chemical Biology·Jinyoung Lee, Matthieu Schapira
Dec 21, 2019·Journal of Medicinal Chemistry·Julien LefrancAntje Margret Wengner
Aug 29, 2019·ACS Omega·Maurice MichelThomas Helleday
Jan 9, 2020·Journal of Medicinal Chemistry·Daniel A ErlansonPaul N Mortenson

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