USP25/28 inhibitor AZ1

USP25/28 inhibitor AZ1 (AZ1) is an orally active, selective, noncompetitive, dual ubiquitin specific protease (USP) 25/28 inhibitor with IC₅₀s of 0.7 μM and 0.6 μM, respectively. High expression levels of USP28 are essential for colon and breast cancers, and stabilization of c-Myc by USP28 is essential for tumor cell proliferation^[5]

USP25/28 inhibitor AZ1-mediated inhibition of USP28 led to changes as measured with predominant effects on pathways associated with cellular stress, cell cycle progression and DNA damage checkpoint and repair. An upregulation of DNA damage sensors like TP53BP1, MRE11 or RAD50 and simultaneously the downregulation of proteins involved in replication-coupled DNA repair, such as RAD51, RPA1 or RPA2^[3]

USP25/28 inhibitor AZ1 attenuates colitis and tumorigenesis in the mice mode^[1].To test the effects of AZ1 on DSS-induced colitis and found that AZ1 gavage protected from weight loss and diarrhea and impaired colon shortening and potentiated the expression of proinflammatory cytokines and antibacterial peptides. In addition, levels of p-p65, p-p38 and SOCS3 were potentiated and levels of TRAF3 and pSTAT3 were decreased in colon tissues from AZ1-treated mice. In addition, gavage of AZ1 maintained weight gain and reduced the bacteria count in feces after C. rodentium infection. inflammation and bacterial replication in the colon were impaired, expression of proinflammatory cytokines and antibacterial peptides was potentiated, levels of p-p65 and p-p38 were increased and levels of TRAF3 were decreased in colons of mice with AZ1 gavage^[2].Subchronic injection of AZ1 in 5 FAD mice markedly ameliorated memory deficits in cued FC and MWM tests.In addition, LTP impairment was reversed through long-term AZ1 administration.AZ1 administration attenuated microglial proliferation and activation in the hippocampusand cortex of 5×FAD mice.AZ1 ameliorated AD neuropathology by attenuating microglial activation^[4]

References:
[1]: Wrigley JD, Gavory G, et,al. Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily. ACS Chem Biol. 2017 Dec 15;12(12):3113-3125. doi: 10.1021/acschembio.7b00334. Epub 2017 Nov 28. PMID: 29131570.
[2]: Wang XM, Yang C, et,al. The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer. Nat Cancer. 2020 Aug;1(8):811-825. doi: 10.1038/s43018-020-0089-4. Epub 2020 Jul 6. PMID: 35122046.
[3]: Prieto-Garcia C, Hartmann O, et,al. Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway. Cell Death Differ. 2022 Mar;29(3):568-584. doi: 10.1038/s41418-021-00875-z. Epub 2021 Oct 5. PMID: 34611298; PMCID: PMC8901929.
[4]: Zheng Q, Li G, et,al. Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25. Sci Adv. 2021 Jan 1;7(1):eabe1340. doi: 10.1126/sciadv.abe1340. PMID: 33523861; PMCID: PMC7775784.
[5]: Popov N, Wanzel M, et,al. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007 Jul;9(7):765-74. doi: 10.1038/ncb1601. Epub 2007 Jun 10. PMID: 17558397.

USP25/28 抑制剂 AZ1 (AZ1) 是一种具有口服活性、选择性、非竞争性的双重泛素特异性蛋白酶 (USP) 25/28 抑制剂，IC₅₀ 分别为 0.7 μM 和 0.6 μM 。 USP28 的高表达水平对于结肠癌和乳腺癌至关重要，USP28 稳定 c-Myc 对于肿瘤细胞增殖至关重要^[5]。

USP25/28 抑制剂 AZ1 介导的 USP28 抑制导致变化，测量结果显示对与细胞应激、细胞周期进程和 DNA 损伤检查点和修复相关的通路有显着影响。上调 TP53BP1、MRE11 或 RAD50 等 DNA 损伤传感器，同时下调参与复制偶联 DNA 修复的蛋白质，例如 RAD51、RPA1 或 RPA2^[3]。

USP25/28 抑制剂 AZ1 在小鼠模型中减轻结肠炎和肿瘤发生^[1]。为了测试 AZ1 对 DSS 诱导的结肠炎的影响，发现 AZ1 管饲可防止体重减轻和腹泻，并且结肠缩短受损并增强促炎细胞因子和抗菌肽的表达。此外，在 AZ1 处理小鼠的结肠组织中，p-p65、p-p38 和 SOCS3 的水平增强，TRAF3 和 pSTAT3 的水平降低。此外，在啮齿类梭菌感染后，灌胃 AZ1 可维持体重增加并减少粪便中的细菌数量。结肠中的炎症和细菌复制受损，促炎细胞因子和抗菌肽的表达增强，p-p65 和 p-p38 水平升高，TRAF3 水平降低，AZ1 灌胃小鼠^[2] 。在 5 只 FAD 小鼠中亚慢性注射 AZ1 显着改善了提示 FC 和 MWM 测试中的记忆缺陷。此外，通过长期给予 AZ1 逆转了 LTP 损伤。AZ1 给药减弱了小鼠海马和皮质中的小胶质细胞增殖和激活5×FAD 小鼠。AZ1 通过减弱小胶质细胞激活改善 AD 神经病理学^[4]。