MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.
Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
Helge
H
Gad
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
Tobias
T
Koolmeister
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
Ann-Sofie
AS
Jemth
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
Saeed
S
Eshtad
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
Sylvain A
SA
Jacques
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
Cecilia E
CE
Ström
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Linda M
LM
Svensson
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Niklas
N
Schultz
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Thomas
T
Lundbäck
Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden.
Berglind Osk
BO
Einarsdottir
Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
Aljona
A
Saleh
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Camilla
C
Göktürk
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden.
Pawel
P
Baranczewski
1] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden.
Richard
R
Svensson
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Ronnie P-A
RP
Berntsson
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Robert
R
Gustafsson
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Kia
K
Strömberg
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Kumar
K
Sanjiv
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Marie-Caroline
MC
Jacques-Cordonnier
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Matthieu
M
Desroses
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Anna-Lena
AL
Gustavsson
Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden.
Roger
R
Olofsson
Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden.
Fredrik
F
Johansson
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Evert J
EJ
Homan
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Olga
O
Loseva
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Lars
L
Bräutigam
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Lars
L
Johansson
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Andreas
A
Höglund
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Anna
A
Hagenkort
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Therese
T
Pham
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Mikael
M
Altun
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden.
Fabienne Z
FZ
Gaugaz
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, S-58185 Linköping, Sweden.
Svante
S
Vikingsson
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.).
Bastiaan
B
Evers
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Martin
M
Henriksson
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Karl S A
KS
Vallin
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Olov A
OA
Wallner
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Lars G J
LG
Hammarström
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Elisee
E
Wiita
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Ingrid
I
Almlöf
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Christina
C
Kalderén
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Hanna
H
Axelsson
1] Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.).
Tatjana
T
Djureinovic
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Jordi Carreras
JC
Puigvert
Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Maria
M
Häggblad
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Fredrik
F
Jeppsson
Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Ulf
U
Martens
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Cecilia
C
Lundin
Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Bo
B
Lundgren
Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
Ingrid
I
Granelli
1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Annika Jenmalm
AJ
Jensen
1] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden.
Per
P
Artursson
Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden.
Jonas A
JA
Nilsson
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Pål
P
Stenmark
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Martin
M
Scobie
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Ulrika Warpman
UW
Berglund
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Thomas
T
Helleday
D000818:Animals; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003460:Crystallization; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009711:Nucleotides / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D023041:Xenograft Model Antitumor Assays; D000096964:Nudix Hydrolases
D045643:DNA Repair Enzymes; D003848:Deoxyguanine Nucleotides; D004791:Enzyme Inhibitors; D009711:Nucleotides; D010744:Phosphoric Monoester Hydrolases; D011743:Pyrimidines; D011755:Pyrophosphatases; D000096964:Nudix Hydrolases; C588302:TH287 compound; C588303:TH588 compound; C078206:8-oxodeoxyguanosine triphosphate; C078207:8-oxodGTPase