HTH-01-015 is a selective NUAK1 inhibitor with IC50 value of 100nM. HTH-01-015 at 10μM inhibited the phosphorylation of the only well-characterized substrate, MYPT1 (myosin phosphate-targeting subunit 1) that is phosphorylated by NUAK1 at Ser-445. HTH-01-015 significantly inhibited MEFs proliferation and migration in a wound-healing assay. HTH-01-015 inhibited the proliferation and impaired the invasive potential of U2OS cells in a 3D cell invasion assay. The 195 site of NUAK1 is important for the inactivation effect of HTH-01-015 for a mutation (A195T) renders NUAK1 ∼50-fold resistant to HTH-01-015[2].
Inhibited NUAK1 activity, reduced phosphorylation of MYPT1 at Ser445
Biochem J. 2014 Jan 1;457(1):215-25.
U2OS cells
3 μM
1000 minutes
Significantly suppressed cells from entering mitosis, an effect comparable to the RO3306 CDK1 inhibitor
Biochem J. 2014 Jul 15;461(2):233-45.
U2OS cells
3 μM
8 hours
Inhibition of NUAK1 activity reduced the population of cells in S-phase by approximately 50%
Biochem J. 2014 Jul 15;461(2):233-45.
Human motor neurons
0.25–32 μM
72 hours
To evaluate the neuroprotective effects of HTH-01-015 in ER stress-mediated neurodegeneration. HTH-01-015 did not rescue CPA toxicity at any of the concentrations tested and was toxic to motor neurons at concentrations above 2 μM even in the absence of CPA.
Cell Chem Biol. 2019 Dec 19;26(12):1703-1715.e37.
HTH-01-015 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
CCl4-induced liver fibrosis model
Intraperitoneal injection
10 or 20 mg/kg
Every other day for 5–8 weeks
To evaluate the therapeutic effect of HTH-01-015 on liver fibrosis
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