TH588 hydrochloride 

TH588 hydrochloride is a highly selective human MTH1 inhibitor (IC₅₀=5 nM) with additional microtubule-targeting properties. TH588 hydrochloride interferes with mitotic progression, induces genomic 8-oxodG formation, DNA damage and cell cycle arrest, and exhibits significant cytotoxicity. Combined with phenethyl isothiocyanate, TH588 hydrochloride enhances ROS-mediated effects and effectively inhibits the growth of visceral metastases of malignant melanoma in mice. TH588 hydrochloride is widely applicable to research related to cancers, pancreatic cancer, leukemia, lymphoma, malignant melanoma and lung cancer^[1][2][3].

TH588 hydrochloride (1-2 µM; 72 h) reduces viability of doxycycline-induced A2780 Pol δ replacement cells, with significantly greater cytotoxicity in cells expressing the error-prone or double mutant Pol δ variants^[1].
TH588 hydrochloride (1 µM; 24 h) induces cleaved PARP signalling in doxycycline-induced A2780 Pol δ replacement cells, with significantly higher levels in cells expressing the error-prone Pol δ variant^[1].
TH588 hydrochloride (2 µM; 24 h) induces caspase-mediated apoptosis in doxycycline-induced A2780 Pol δ replacement cells, with significantly higher apoptosis in cells expressing the error-prone Pol δ variant^[1].
TH588 hydrochloride (5 µM; 16 h) triggers mitotic DNA replication in U2OS cells when pre-incubated with RO3306, resulting in a significant increase in mitotic cells with EdU foci^[1].
TH588 hydrochloride (0.1-10 µM; 72 h) reduces viability of U2OS cells in a dose-dependent manner, and this cytotoxicity is completely prevented by co-treatment with reversine^[1].
TH588 hydrochloride (2-6 μM; 5 days) concentration-dependently inhibits the growth of human pancreatic cancer Panc-1 cells over 5 days, and this effect is independent of oxidative stress^[2].
TH588 hydrochloride (1-3 μM; 7 days) significantly enhances H₂O₂-induced growth inhibition of human pancreatic cancer Panc-1 cells over 7 days, despite having no effect on cell growth when used alone^[2].
TH588 hydrochloride (1-3 μM; 5 days) significantly enhances doxorubicin-induced growth inhibition of human pancreatic cancer MIAPaCa-2 cells over 5 days^[2].
TH588 hydrochloride (1-3 μM; 5 days) significantly enhances PEITC-induced growth inhibition of human pancreatic cancer MIAPaCa-2 cells over 5 days, with the combination showing greater efficacy than other ROS inducer-TH588 pairings^[2].
TH588 hydrochloride (2 μM; 2 days), combined with 4 μM PEITC, induces caspase-dependent cell death in human pancreatic cancer MIAPaCa-2 cells over 2 days^[2].
TH588 hydrochloride (0.2-0.6 μM; 5 days) significantly enhances PEITC-induced growth inhibition of human leukemia NB4 cells over 5 days, regardless of relatively low MTH1 mRNA expression^[2].
TH588 hydrochloride (0.2-0.6 μM; 5 days) significantly enhances PEITC-induced growth inhibition of human lymphoma BALM3 cells over 5 days^[2].
TH588 hydrochloride (1-2 μM; 56 hours) induces nuclear formation of 8-oxo-dG and pH2AX (markers of oxidative DNA damage) in human pancreatic cancer MIAPaCa-2 cells after 56 hours of incubation^[2].
TH588 hydrochloride (0.4 μM; 56 hours), combined with 2 μM PEITC, cooperatively induces nuclear formation of 8-oxo-dG and γH2AX foci in human pancreatic cancer MIAPaCa-2 cells after 56 hours of incubation^[2].
TH588 hydrochloride (1-8 µM; 2 hours) concentration-dependently disrupts centrosome separation, spindle bipolarity, and chromosome congression in unsynchronized mitotic H460 human lung cancer cells, with 4 µM inducing monopolar spindles in over 50% of mitotic cells^[3].
TH588 hydrochloride (4-6 µM; 24 hours) induces G2/M phase cell cycle arrest in H460 human lung cancer cells, with 4 µM increasing G2/M phase cells to ~42% and 6 µM increasing G2/M phase cells to ~35%^[3].
TH588 hydrochloride (4-7 µM; 48 total hours) concentration-dependently induces G1 arrest and prevents cell cycle re-entry in H460 human lung cancer cells, with 7 µM causing G1 arrest in ~70% of cells^[3].
TH588 hydrochloride (6 µM; 48 total hours) shows that TP53 and USP28 are required for TH588-induced G₁ arrest in H460 human lung cancer cells, with TP53 knockout reducing 6 µM TH588-induced G₁ arrest from ~40% to ~10%^[3].
TH588 hydrochloride (2-8 µM; 24 hours) concentration-dependently increases p53 levels in H460 human lung cancer cells, and this activation is dependent on USP28, as USP28-knockout clones show no p53 induction^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

TH588 hydrochloride enhances 8-oxodGTP (HY-112817)-induced embryonic toxicity in zebrafish, especially in the absence of MTH1^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

331.63

C₁₃H₁₃Cl₃N₄

1640282-30-9

NC1=NC(C2=CC=CC(Cl)=C2Cl)=CC(NC3CC3)=N1.[H]Cl

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Rudd SG, et al. MTH1 Inhibitor TH588 Disturbs Mitotic Progression and Induces Mitosis-Dependent Accumulation of Genomic 8-oxodG. Cancer Res. 2020;80(17):3530-3541.  [Content Brief]

  [2]. Ikejiri F, et al. TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells. Oncol Lett. 2018;15(3):3240-3244.  [Content Brief]

  [3]. Gul N, et al. The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway. Sci Rep. 2019;9(1):14667. Published 2019 Oct 11.  [Content Brief]