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.
IU1是一种细胞可渗透的、可逆的选择性蛋白酶体抑制剂，对USP14的 IC50 为 4.7μM。IU1通过结合USP14的催化裂口抑制USP14，从而阻断其酶活性。用IU1处理细胞可增强与神经退行性疾病有关的几种蛋白酶体底物的降解[1-2]。
IU1(25μM)处理通过调节ZO-1表达，可以缓解OGD（缺氧/复氧损伤）在培养的Bend.3细胞中诱导的内皮细胞渗漏[3]。通过IU1(100μM; 8h)抑制USP14活性可以显著降低胃癌细胞MKN74的活力，并抑制其迁移和侵袭能力[4] 。此外，IU1(1-100μM; 24h)以剂量依赖的方式显著减少了ML1细胞的增殖和迁移能力[5] 。
IU1(400μg/kg; i.p; 3 times)通过抑制USP14，在MCAO（大脑中动脉闭塞）小鼠中保护血脑屏障完整性并减轻神经炎症，从而促进康复[3]。IU1(p.o; 40mg/kg/d; 14 days)耗竭USP14能抑制小鼠肝细胞癌（HCC）细胞的生长[6]。IU1 (400μg/kg; i.p; 7days)处理能减轻缺血性中风引起的神经元损伤，这体现在IU1处理组小鼠生存率提高、梗死体积减少以及神经元丢失减少上[7]。