| 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
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.
Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.,Rahm F, Viklund J, Tresaugues L, Ellermann M, Giese A, Ericsson U, Forsblom R, Ginman T, Gunther J, Hallberg K, Lindstrom J, Persson LB, Silvander C, Talagas A, Diaz-Saez L, Fedorov O, Huber KVM, Panagakou I, Siejka P, Gorjanacz M, Bauser M, Andersson M J Med Chem. 2018 Mar 7. doi: 10.1021/acs.jmedchem.7b01884. PMID:29485874[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Rahm F, Viklund J, Tresaugues L, Ellermann M, Giese A, Ericsson U, Forsblom R, Ginman T, Gunther J, Hallberg K, Lindstrom J, Persson LB, Silvander C, Talagas A, Diaz-Saez L, Fedorov O, Huber KVM, Panagakou I, Siejka P, Gorjanacz M, Bauser M, Andersson M. Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design. J Med Chem. 2018 Mar 7. doi: 10.1021/acs.jmedchem.7b01884. PMID:29485874 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01884
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