LDN 57444 is a small molecular inhibitor that can block UCHL1 deubiquitinase activity (Ki=0.40μM; IC50=0.88μM), with an IC50 value of 25μM for inhibiting UCHL3 [1]. LDN 57444 suppresses mouse oocyte maturation by improving oxidative stress, attenuating mitochondrial function, curbing spindle body formation and down-regulating extracellular signal-related kinases (ERK1/2) expression [2]. LDN 57444 has been widely used to inhibit the invasive ability of nasopharyngeal cancer cells and reduce the adhesion of cancer cells[3].
In vitro, LDN 57444 treatment (50μM) for 24 hours significantly triggered apoptosis in SK-N-SH cells and inhibited the ubiquitin-proteasome system and induced endoplasmic reticulum stress[4]. Treatment with 10μM LDN 57444 for 24 hours significantly inhibited the migration of human dermal fibroblasts (HDFs) and upregulated the phosphorylation of Smad2 and Smad3[5].
In vivo, LDN 57444 treatment via daily intraperitoneal injection at a dose of 40μg/kg for 3 weeks significantly reduced atrial fibrillation induced by angiotensin II in mice[6]. Daily intraperitoneal injection of 5mg/kg dose of LDN 57444 for 14 days can result in a reduced number of metastatic foci in the lungs and liver of mice with DU-145 xenograft tumors[7]. Daily intraperitoneal injection of 20μg/kg dose of LDN 57444 for 4 months can lower the blood pressure of spontaneously hypertensive rats and improve the cardiac function[8].
References:
[1] Liu Y, Lashuel H A, Choi S, et al. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line[J]. Chemistry & biology, 2003, 10(9): 837-846.
[2] Yuan P, Zhou L, Zhang X, et al. UCH-L1 inhibitor LDN-57444 hampers mouse oocyte maturation by regulating oxidative stress and mitochondrial function and reducing ERK1/2 expression[J]. Bioscience Reports, 2020, 40(10): BSR20201308.
[3] Kobayashi E, Hwang D, Bheda-Malge A, et al. Inhibition of UCH-L1 deubiquitinating activity with two forms of LDN-57444 has anti-invasive effects in metastatic carcinoma cells[J]. International journal of molecular sciences, 2019, 20(15): 3733.
[4] Tan Y Y, Zhou H Y, Wang Z Q, et al. Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor[J]. Molecular and cellular biochemistry, 2008, 318(1): 109-115.
[5] Pan H, Song J, An Q, et al. Inhibition of Ubiquitin C‐Terminal Hydrolase L1 Facilitates Cutaneous Wound Healing via Activating TGF‐β/Smad Signalling Pathway in Fibroblasts[J]. Experimental Dermatology, 2024, 33(10): e15186.
[6] Bi H L, Zhang Y L, Yang J, et al. Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice[J]. Hypertension Research, 2020, 43(3): 168-177.
[7] Liu S, Garcia-Marques F J, Shen M, et al. Ubiquitin C-terminal hydrolase L1 is a regulator of tumor growth and metastasis in double-negative prostate cancer[J]. American Journal of Clinical and Experimental Urology, 2024, 12(5): 306.
[8] Han X, Zhang Y L, Fu T, et al. Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats[J]. Hypertension Research, 2020, 43(10): 1089-1098.
LDN 57444是一种小分子抑制剂，可阻断UCHL1的去泛素化酶活性（Ki=0.40μM；IC50=0.88μM），抑制UCHL3的IC50值为25μM[1]。LDN 57444通过加剧氧化应激、减弱线粒体功能、抑制纺锤体形成和下调细胞外信号调节激酶(ERK1/2)的表达，从而抑制小鼠卵母细胞的成熟[2]。LDN 57444已被广泛用于抑制鼻咽癌细胞的侵袭能力并降低癌细胞的粘附[3]。
在体外，50μM的LDN 57444处理SK-N-SH细胞24小时，显著触发了细胞凋亡，抑制了泛素-蛋白酶体系统并诱导了内质网应激[4]。10μM的LDN 57444处理人真皮成纤维细胞(HDFs) 24小时，显著抑制了细胞迁移，并上调了Smad2和Smad3的磷酸化[5]。
在体内，每日腹腔注射40μg/kg剂量的LDN 57444，持续3周，显著减少了血管紧张素II诱导的小鼠心房颤动[6]。每日腹腔注射5mg/kg剂量的LDN 57444，持续14天，可导致DU-145异种移植瘤小鼠肺和肝中的转移灶数量减少[7]。每日腹腔注射20μg/kg剂量的LDN 57444，持续4个月，可降低自发性高血压大鼠的血压并改善心脏功能[8]。