TH588 hydrochloride是一种MTH1（NUDT1；IC50=5nM）抑制剂。
Cas No.:1640282-30-9
Sample solution is provided at 25 µL, 10mM.
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TH588 hydrochloride is an inhibitor of MTH1 (NUDT1; IC50=5nM)[1-2]. TH588 hydrochloride works by inhibiting MTH1 to prevent cancer cells from clearing oxidized nucleotides, thereby inducing DNA damage and activating the ATM-p53-mediated cell death response and DNA repair. TH588 hydrochloride can be used in research related to lung adenocarcinoma, breast cancer, colon cancer, and melanoma[3-4].
In vitro, TH588 hydrochloride (5-30µM) was used to treat cell lines such as U2OS, HeLa, and RPE-1 for 0 to 4 hours. By inhibiting tubulin polymerization and microtubule dynamics, TH588 hydrochloride significantly suppressed microtubule turnover within the mitotic spindle, leading to chromosome congression defects. TH588 hydrochloride resulted in mitotic arrest, cell death, or cell division with incorrectly aligned chromosomes[5]. TH588 hydrochloride (1–8µM) was applied to H460 human lung cancer cells, U2OS osteosarcoma cells, HeLa, and other cell lines for 0 to 48 hours. TH588 hydrochloride significantly prolonged the duration of mitosis and, by activating the USP28-p53-mediated mitotic surveillance pathway, caused cell cycle arrest in the G1 phase of the subsequent cycle[6].
In vivo, TH588 hydrochloride (50µM) and the photosensitizer Ce6 (20µM) were co-loaded into the nanocarrier T&C@SCLMs. This formulation was administered via tail vein injection (0.2ml; once every 5 days; for a total of 20 days) to nude mice bearing A431 solid tumors. TH588 hydrochloride significantly enhanced the efficacy of photodynamic therapy (PDT), resulting in reduced tumor volume and inducing a higher proportion of tumor cell apoptosis[7]. TH588 hydrochloride (30mg/kg) was administered via daily subcutaneous injection for 2 to 3 weeks to BALB/c-nu nude mice bearing xenografts of MCF7, MDA-MB-231, or MDA-MB-453 human breast cancer cells. TH588 hydrochloride significantly suppressed tumor growth without causing significant hematological or liver function toxicity[8].
References:
[1] Gad H, Koolmeister T, Jemth AS, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014 Apr 10;508(7495):215-21.
[2] Ikejiri F, Honma Y, Kasukabe T, et al. TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells. Oncol Lett. 2018 Mar;15(3):3240-3244.
[3] Wang JY, Jin L, Yan XG, et al. Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588. J Invest Dermatol. 2016 Nov;136(11):2277-2286.
[4] Pompsch M, Vogel J, Classen F, et al. The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia. BMC Cancer. 2018 Nov 29;18(1):1190.
[5] Rajendraprasad G, Eibes S, Boldú CG, et al. TH588 and Low-Dose Nocodazole Impair Chromosome Congression by Suppressing Microtubule Turnover within the Mitotic Spindle. Cancers (Basel). 2021 Nov 29;13(23):5995.
[6] Gul N, Karlsson J, Tängemo C, et al. The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway. Sci Rep. 2019 Oct 11;9(1):14667.
[7] Zhao L, Li J, Su Y, et al. MTH1 inhibitor amplifies the lethality of reactive oxygen species to tumor in photodynamic therapy. Sci Adv. 2020 Mar 4;6(10):eaaz0575.
[8] Zhang X, Song W, Zhou Y, et al. Expression and function of MutT homolog 1 in distinct subtypes of breast cancer. Oncol Lett. 2017 Apr;13(4):2161-2168.
TH588 hydrochloride是一种MTH1（NUDT1；IC50=5nM）抑制剂[1-2]。TH588 hydrochloride通过抑制MTH1来防止癌细胞清除氧化的核苷酸，从而诱导DNA损伤、激活ATM-p53介导的死亡应答和DNA修复。TH588 hydrochloride可用于肺腺癌、乳腺癌、结肠癌和黑色素瘤等相关研究[3-4]。
在体外，TH588 hydrochloride（5-30μM）处理U2OS、HeLa及RPE-1等细胞系0至4小时。TH588 hydrochloride通过抑制微管蛋白聚合和微管动力学，显著抑制了有丝分裂纺锤体内的微管翻转，导致染色体排列障碍，最终引发有丝分裂停滞、细胞死亡或发生染色体未正确排列的细胞分裂[5]。TH588 hydrochloride（1–8μM）处理H460人肺癌细胞、U2OS骨肉瘤细胞及HeLa等细胞系数0至48小时，TH588 hydrochloride显著延长了细胞有丝分裂时间，同时通过激活USP28-p53介导的有丝分裂监视通路，导致细胞在下一细胞周期的G1期发生停滞[6]。
在体内，TH588 hydrochloride（50μM）与光敏剂Ce6（20μM）共载于纳米载体T&C@SCLMs中，通过尾静脉注射给药（0.2ml；每5天一次；共20天），用于处理携带A431实体瘤的裸鼠。TH588 hydrochloride显著增强了光动力疗法（PDT）的疗效，导致肿瘤体积缩小，并诱导了更高比例的肿瘤细胞凋亡[7]。TH588 hydrochloride（30mg/kg）每日皮下注射，用于处理携带MCF7、MDA-MB-231或MDA-MB-453人乳腺癌细胞异种移植瘤的BALB/c-nu裸鼠，连续2到3周。TH588 hydrochloride显著抑制了肿瘤生长，同时未引起显著的血液学或肝功能毒性[8]。
| Cell experiment [1]: | |
Cell lines | H460 human lung cancer cells, U2OS osteosarcoma cells, and HeLa cells |
Preparation Method | Cells were maintained in Dulbecco's modified eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and antibiotics at 37°C, 5% CO₂. Cells were treated with TH588 hydrochloride (1-8μM) for 0-48 hours. |
Reaction Conditions | 1-8μM; 0-48 hours. |
Applications | TH588 hydrochloride rapidly reduced microtubule plus-end mobility, disrupted mitotic spindle assembly and chromosome congression, and prolonged mitosis in a concentration-dependent manner. TH588 hydrochloride activated the USP28-p53 mitotic surveillance pathway, leading to cell cycle arrest in the G1 phase of the subsequent cycle. These effects were independent of its intended target, MTH1 inhibition. |
| Animal experiment [2]: | |
Animal models | Female BALB/c-nu nude mice with MCF7, MDA-MB-231, or MDA-MB-453 human breast cancer cell xenografts |
Preparation Method | Mice were inoculated subcutaneously with cancer cells. After tumors reached a visible size (~2mm in mean diameter), mice were administered daily subcutaneous injections of TH588 hydrochloride (30mg/kg) or vehicle control for 2-3 weeks. |
Dosage form | 30mg/kg; s.c.; daily for 2-3 weeks. |
Applications | TH588 hydrochloride treatment significantly suppressed tumor growth, causing over 90% regression in MCF7 and MDA-MB-231 tumors and completely eradicating MDA-MB-453 tumors. TH588 hydrochloride also inhibited mouse body weight gain, although no significant hematological or liver function toxicity was observed. |
References: | |
| Cas No. | 1640282-30-9 | SDF | |
| Canonical SMILES | NC1=NC(C2=CC=CC(Cl)=C2Cl)=CC(NC3CC3)=N1.[H]Cl | ||
| 分子式 | C13H13Cl3N4 | 分子量 | 331.63 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0154 mL | 15.077 mL | 30.1541 mL |
| 5 mM | 603.1 μL | 3.0154 mL | 6.0308 mL |
| 10 mM | 301.5 μL | 1.5077 mL | 3.0154 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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- Purity: >98.00% Appearance: A solid
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