- Radiolabeled 6-(2, 3-dichlorophenyl)-n4-methylpyrimidine-2, 4-diamine (th287): A potential radiotracer for measuring and imaging mth1
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MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic assays show that TH287 has an IC50 of 2.2 nM in inhibiting MTH1 hydrolase activity and a Ki of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [11C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders.
- Chen, Huaping,Afrin, Sadia,Guo, Yingqiu,Chu, Wenhua,Benzinger, Tammie L. S.,Rogers, Buck E.,Garbow, Joel R.,Perlmutter, Joel S.,Zhou, Dong,Xu, Jinbin
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- Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation
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We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystallization of 5 with MTH1 revealed the ligand in a φ-cis-N-(pyridin-2-yl)acetamide conformation enabling a key intramolecular hydrogen bond and polar interactions with residues Gly34 and Asp120. Modification of literature compound TH287 with O- and N-linked aryl and alkyl aryl substituents led to the discovery of potent pyrimidine-2,4,6-triamine 25 (IC50 = 0.49 nM). Triazolopyridine 32 emerged as a highly selective lead compound with a suitable in vitro profile and desirable pharmacokinetic properties in rat. Elucidation of the DNA damage response, cell viability, and intracellular concentrations of oxo-NTPs (oxidized nucleoside triphosphates) as a function of MTH1 knockdown and/or small molecule inhibition was studied. Based on our findings, we were unable to provide evidence to further pursue MTH1 as an oncology target.
- Farand, Julie,Kropf, Jeffrey E.,Blomgren, Peter,Xu, Jianjun,Schmitt, Aaron C.,Newby, Zachary E.,Wang, Ting,Murakami, Eisuke,Barauskas, Ona,Sudhamsu, Jawahar,Feng, Joy Y.,Niedziela-Majka, Anita,Schultz, Brian E.,Schwartz, Karen,Viatchenko-Karpinski, Serge,Kornyeyev, Dmytro,Kashishian, Adam,Fan, Peidong,Chen, Xiaowu,Lansdon, Eric B.,Ports, Michael O.,Currie, Kevin S.,Watkins, William J.,Notte, Gregory T.
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p. 358 - 364
(2019/12/02)
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- Pyrimidines compound and preparation method and application thereof
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The invention discloses a pyrimidines compound. The structure of the pyrimidines compound is shown in a formula (I) as shown in the specification, in the formula, R1 is selected from one of hydrogen, halogen, nitro, cyano, hydroxyl, amino, dimethylamino, Cl-6 alkyl, Cl-6 perfluoroalkyls, C2-6 alkenyls, C2-6 alkynyls, C3-6 cycloalkyl, C3-12 heteroalicyclyl or Cl-6 alkoxy, R2 is selected from one of hydrogen, Cl-6 alkyl, C2-6 alkenyls, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyloxy, C3-12 heteroalicyclyl, aryl, substituted aryl or a group P, the group P is as shown in the specification, R3 is selected from hydrogen or a group Q, the group Q is as shown in the specification, X is selected from one of Q, S, N or -NHCO-, at least one of the group P and the group Q appears, m is 1-7, and n is 1-7. The pyrimidines compound is 8-hydroxyguanine nucleotidase inhibitor, and can be used for treating diseases caused by abnormity of activity of 8-hydroxyguanine nucleotidase, such as tumors.
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Paragraph 0190-0192
(2017/08/30)
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- MTH1 INHIBITORS FOR TREATMENT OF CANCER
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A compound of formula I, (I) or a pharmaceutically-acceptable salt thereof. The compound is useful in the treatment of cancer.
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Page/Page column 41
(2015/12/30)
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- MTH1 INHIBITORS FOR TREATMENT OF INFLAMMATORY AND AUTOIMMUNE CONDITIONS
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A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of autoimmune diseases and inflammatory conditions.
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Page/Page column 70; 71
(2016/04/04)
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