TH588

TH588 is an inhibitor of MTH1 (NUDT1; IC₅₀=5nM)^[1-2]. TH588 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 can be used in research related to lung adenocarcinoma, breast cancer, colon cancer, and melanoma^[3-4].

In vitro, TH588 (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 significantly suppressed microtubule turnover within the mitotic spindle, leading to chromosome congression defects. TH588 resulted in mitotic arrest, cell death, or cell division with incorrectly aligned chromosomes^[5]. TH588 (1–8µM) was applied to H460 human lung cancer cells, U2OS osteosarcoma cells, HeLa, and other cell lines for 0 to 48 hours. TH588 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 (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 significantly enhanced the efficacy of photodynamic therapy (PDT), resulting in reduced tumor volume and inducing a higher proportion of tumor cell apoptosis^[7]. TH588 (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 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是一种MTH1（NUDT1；IC₅₀=5nM）抑制剂^[1-2]。TH588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（5-30μM）处理U2OS、HeLa及RPE-1等细胞系0至4小时。TH588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（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（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（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]。