| Structural highlights
Function
8ODP_HUMAN Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.
Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target.,Ellermann M, Eheim A, Rahm F, Viklund J, Guenther J, Andersson M, Ericsson U, Forsblom R, Ginman T, Lindstrom J, Silvander C, Tresaugues L, Giese A, Bunse S, Neuhaus R, Weiske J, Quanz M, Glasauer A, Nowak-Reppel K, Bader B, Irlbacher H, Meyer H, Queisser N, Bauser M, Haegebarth A, Gorjanacz M ACS Chem Biol. 2017 Aug 18;12(8):1986-1992. doi: 10.1021/acschembio.7b00370. Epub, 2017 Jul 12. PMID:28679043[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fujikawa K, Kamiya H, Yakushiji H, Fujii Y, Nakabeppu Y, Kasai H. The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein. J Biol Chem. 1999 Jun 25;274(26):18201-5. PMID:10373420
- ↑ Fujii Y, Shimokawa H, Sekiguchi M, Nakabeppu Y. Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins. J Biol Chem. 1999 Dec 31;274(53):38251-9. PMID:10608900
- ↑ Fujikawa K, Kamiya H, Yakushiji H, Nakabeppu Y, Kasai H. Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res. 2001 Jan 15;29(2):449-54. PMID:11139615
- ↑ Yoshimura D, Sakumi K, Ohno M, Sakai Y, Furuichi M, Iwai S, Nakabeppu Y. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem. 2003 Sep 26;278(39):37965-73. Epub 2003 Jul 10. PMID:12857738 doi:10.1074/jbc.M306201200
- ↑ Takagi Y, Setoyama D, Ito R, Kamiya H, Yamagata Y, Sekiguchi M. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem. 2012 Jun 15;287(25):21541-9. doi: 10.1074/jbc.M112.363010. Epub 2012, May 3. PMID:22556419 doi:10.1074/jbc.M112.363010
- ↑ Ellermann M, Eheim A, Rahm F, Viklund J, Guenther J, Andersson M, Ericsson U, Forsblom R, Ginman T, Lindstrom J, Silvander C, Tresaugues L, Giese A, Bunse S, Neuhaus R, Weiske J, Quanz M, Glasauer A, Nowak-Reppel K, Bader B, Irlbacher H, Meyer H, Queisser N, Bauser M, Haegebarth A, Gorjanacz M. Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target. ACS Chem Biol. 2017 Aug 18;12(8):1986-1992. doi: 10.1021/acschembio.7b00370. Epub, 2017 Jul 12. PMID:28679043 doi:http://dx.doi.org/10.1021/acschembio.7b00370
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