title: Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival.
abstract: Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Kettle
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Husam
authors.initials: H
authors.lastname: Alwan
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Michal
authors.initials: M
authors.lastname: Bista
authors.affiliation: Discovery Sciences, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Nichola L
authors.initials: NL
authors.lastname: Davies
authors.affiliation: Discovery Sciences, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Kay
authors.initials: K
authors.lastname: Eckersley
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Shaun
authors.initials: S
authors.lastname: Fillery
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Foote
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Goodwin
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Discovery Sciences, AstraZeneca , Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Käck
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: J Willem M
authors.initials: JW
authors.lastname: Nissink
authors.affiliation: Discovery Sciences, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.affiliation: Discovery Sciences, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Ben
authors.initials: B
authors.lastname: Taylor
authors.affiliation: Discovery Sciences, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Walker
authors.affiliation: Discovery Sciences, AstraZeneca , Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wissler
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Wylot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes