HOIPIN-8 is a potent inhibitor of the linear ubiquitin chain assembly complex (LUBAC) with an IC₅₀ of 11nM [1]. LUBAC is an E3 ubiquitin ligase complex that specifically generates M1-linked linear polyubiquitin chains. It is composed of HOIL-1L, HOIP, and SHARPIN. LUBAC activates the NF-κB pathway and inhibits apoptosis via the linear ubiquitination of various substrates[2].
HOIPIN-8 (30μM) treatment of A431, MCF-7, and MDA-MB-231 cancer cells for 2h reduced the phosphorylation levels of both IκBα and p65 compared with the DMSO-treated group, along with a significant decrease in cell proliferation rates, demonstrating HOIPIN-8's ability to inhibit both NF-κB pathway activation and cancer cell proliferation[3]. Similarly, treatment with HOIPIN-8 (100μM) for 48h significantly reduced both proliferation rates and invasive capabilities in HepG2 and Hep3B cancer cell lines[4]. The TDP-43 A315T mutation, associated with amyotrophic lateral sclerosis (ALS), enhances TDP-43 protein aggregation. In Neuro2a cells expressing TDP-43 A315T247-414-GFP, treatment with HOIPIN-8(10μM) for 20h significantly reduced protein aggregation compared to untreated controls[5].
HOIPIN-8 (30μM) treatment of human pancreatic organoids (hPOs) for 30min effectively delayed BV6-induced organoid disintegration, prevented luminal structure collapse, and extended survival duration[6].
References:
[1] Katsuya K, Oikawa D, Iio K, et al., Small-molecule inhibitors of linear ubiquitin chain assembly complex (LUBAC), HOIPINs, suppress NF-κB signaling, Biochemical and Biophysical Research Communications[J]. 2019, 509: 700-706.
[2] Tokunaga F, Iwai K, LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses, Microbes and Infection[J]. 2012, 14: 563-572.
[3] Hua F, Hao W, Wang L, et al., Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development, Int J Mol Sci[J]. 2021, 22: 11875.
[4] Hoshino K, Nakazawa S, Yokobori T, et al., RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation, Scientific Reports[J]. 2024, 14: 346.
[5] Zhang Q, Terawaki S, Oikawa D, et al., Suppression of Linear Ubiquitination Ameliorates Cytoplasmic Aggregation of Truncated TDP-43, Cells[J]. 2022, 11: 2398.
[6] Weinelt N, Wächtershäuser K N, Celik G, et al., LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL, Cell Death & Disease[J]. 2024, 15: 77.
HOIPIN-8是一种高效的线性泛素链组装复合体（LUBAC）的抑制剂，其IC50为11nM[1]。LUBAC是一种E3泛素连接酶复合体，能够特异性催化M1连接的线性多聚泛素链的形成。该复合体由HOIL-1L、HOIP和SHARPIN组成。LUBAC通过对多种底物进行线性泛素化来激活 NF-κB 信号通路，并抑制细胞凋亡[2]。
HOIPIN-8（30μM）处理A431, MCF-7, and MDA-MB-231癌细胞2h，与DMSO处理组相比，IκBɑ以及p65的磷酸化水平下降，同时细胞增殖速率明显下降，表明HOIPIN-8能够抑制NF-κB通路的激活以及癌细胞增殖[3]。类似地，HOIPIN-8（100μM）处理HepG2和Hep3B癌细胞48小时，癌细胞增殖速率和侵袭能力明显下降[4]。TDP-43 A315T突变是一种和肌萎缩侧索硬化（ALS）相关的突变，它能够使得TDP-43蛋白聚集增加。在Neuro2a细胞中表达TDP-43 A315T247-414-GFP，使用HOIPIN-8（10μM）处理细胞20h，和未处理细胞相比，蛋白的聚集明显减少[5]。
HOIPIN-8（30μM）处理人类胰腺类器官（hPOs）30min，可以有效延缓BV6诱导的类器官崩溃，防止腔体形态的丧失，延长hPOs的存活时间[6]。