IU1 is a cytopermeable, reversible selective inhibitor of proteasome with an IC50 of 4.7μM for USP14. IU1 inhibits USP14 by binding to the catalytic cleft in USP14 thus blocking its enzyme activity. Treatment of cultured cells with IU1 enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease [1-2].
IU1(25μM) treatment could alleviate endothelial cell leakage induced by OGD in cultured Bend.3 cells through modulating ZO-1 expression[3]. Inhibition of USP14 activity by IU1(100μM; 8h) can significantly reduce the viability of gastric cancer cells MKN74 and inhibit their migration and invasion ability[4]. IU1(1-100μM; 24h) caused a significant decrease in cell proliferation and migration of ML1 cells in a dose dependent manner[5].
IU1(400μg/kg; i.p; 3 times) promotes recovery by protecting the integrity of the blood-brain barrier and alleviating neuroinflammation in MCAO mice by inhibiting USP14[3]. USP14 depletion by IU1(p.o; 40mg/kg/d; 14 days) suppresses Hepatocellular carcinoma (HCC) cell growth in mice[6]. IU1(400μg/kg; i.p; 7days) treatment attenuated ischemic stroke-caused neuronal injury, which was reflected by increased survival rate, reduced infarct volume, as well as decreased neuronal loss in the IU1-treated mice[7].
References:
[1]. Lee BH, Lee MJ, et,al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010 Sep 9;467(7312):179-84. doi: 10.1038/nature09299. PMID: 20829789; PMCID: PMC2939003.
[2]. Abramson HN. The Multiple Myeloma Drug Pipeline-2018: A Review of Small Molecules and Their Therapeutic Targets. Clin Lymphoma Myeloma Leuk. 2018 Sep;18(9):611-627. doi: 10.1016/j.clml.2018.06.015. Epub 2018 Jun 18. PMID: 30001985.
[3]. Hou W, Yao J, et,al. USP14 inhibition promotes recovery by protecting BBB integrity and attenuating neuroinflammation in MCAO mice. CNS Neurosci Ther. 2023 Nov;29(11):3612-3623. doi: 10.1111/cns.14292. Epub 2023 Jun 2. PMID: 37269080; PMCID: PMC10580339.
[4]. Lee MY, Kim MJ, et,al.USP14 inhibition regulates tumorigenesis by inducing apoptosis in gastric cancer. BMB Rep. 2023 Aug;56(8):451-456. doi: 10.5483/BMBRep.2023-0063. PMID: 37401238; PMCID: PMC10471464.
[5]. Srinivasan V, Asghar MY, et,al. Proliferation and migration of ML1 follicular thyroid cancer cells are inhibited by IU1 targeting USP14: role of proteasome and autophagy flux. Front Cell Dev Biol. 2023 Aug 30;11:1234204. doi: 10.3389/fcell.2023.1234204. PMID: 37711852; PMCID: PMC10499180.
[6]. Lv C, Wang S, et,al. USP14 maintains HIF1-α stabilization via its deubiquitination activity in hepatocellular carcinoma. Cell Death Dis. 2021 Aug 21;12(9):803. doi: 10.1038/s41419-021-04089-6. PMID: 34420039; PMCID: PMC8380251.
[7].Min JW, Lü L, et,al. USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice. J Neurochem. 2017 Mar;140(5):826-833. doi: 10.1111/jnc.13941. Epub 2017 Jan 26. PMID: 28029679; PMCID: PMC5527549.