P005091 is a potent and selective ubiquitin-specific proteinase 7 (USP7) inhibitor with an EC50 value of 4.2 μM[1]. P005091 is a trisubstituted thiophene with dichlorophenylthio, nitro, and acetyl substituents that mediates anti-USP7 activity and may be a potential therapeutic agent for the treatment of HO-1-overexpressing liver cancer [2]. P005091 can inhibit the development of hepatoblastoma and the PI3K/AKT pathway [3].
In vitro, treatment of multiple myeloma cell lines with P005091 (12.5μM) for 24 hours resulted in a decrease in cell viability and inhibited USP7 deubiquitination activity in MM cells without blocking proteasome activity [1]. P005091 (3μM) treated MM.1S cells for 12 hours induced cytotoxicity, accompanied by the upregulation of p53 and p21[4]. P005091 (10 μM) treated CUTLL1 and JURKAT cells for 24 hours, which significantly increased the polyubiquitination of SF3B1 protein and reduced the level of SF3B1 protein [5].
In vivo, intraperitoneal injection of P005091 (10mg/kg) in tumor-bearing mice significantly inhibited tumor cell growth and reduced PCNA protein expression in tumor cells [6]. P005091 treatment also reduced IL-10 mRNA levels in tumor tissue while increasing IFN-γ and TNF-α mRNA levels [6]. Tail vein injection of P005091 (10mg/kg) significantly reduced the protein level of MyD88 in mouse cells [7].
References:
[1] Chauhan D, et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance[J]. Cancer Cell. 2012 Sep 11;22(3):345-58.
[2] Gao M , Qi Z , Deng M ,et al.The deubiquitinase USP7 regulates oxidative stress through stabilization of HO-1[J].Oncogene, 2022(33):41.
[3] Ye M , He J , Zhang J ,et al. USP7 promotes hepatoblastoma progression through activation PI3K/AKT signaling pathway[J].Cancer biomarkers : section A of Disease markers.2021.
[4] Das D S , Ray A , Das A ,et al.A Novel Hypoxia-Selective Epigenetic Agent RRx-001 Triggers Apoptosis and Overcomes Drug Resistance in Multiple Myeloma Cells[J]. Leukemia Research Fund, U.K, 2016, 30(11).
[5]Han C , Khodadadi-Jamayran A , Lorch A H ,et al. SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia[J].Science advances, 2022, 8(3):eabj8357.
[6]Fu C, Zhu X , Xu P ,et al. Pharmacological inhibition of USP7 promotes antitumor immunity and contributes to colon cancer therapy[J].OncoTargets and Therapy, 2019, Volume 12:609-617.
[7]Na Zhang, Fei Wang, et al. USP7 Promotes deubiquitination and stabilization of MyD88 to enhance immune responses[J].Front. Immunol., 12 August 2022.
P005091是一种有效的选择性泛素特异性蛋白酶7 (USP7) 抑制剂，EC50 值为4.2 μM[1]。P005091是一种三取代噻吩，具有二氯苯硫基、硝基和乙酰取代基，介导抗USP7活性，可能是治疗HO-1过表达肝癌的潜在治疗剂[2]。P005091可抑制肝母细胞瘤的发展和PI3K/AKT通路[3]。
在体外，P005091（12.5μM）处理多发性骨髓瘤细胞系24h，会导致细胞活力下降，抑制MM细胞中的USP7去泛素化活性，而不阻断蛋白酶体活性[1]。P005091（3μM）处理MM.1S细胞12小时诱导了细胞毒性，伴随p53和p21的上调[4]。P005091（10 μM）处理CUTLL1和JURKAT细胞24h，使SF3B1蛋白的多泛素化显著增加，降低了SF3B1蛋白的水平[5]。
在体内，P005091（10mg/kg）腹膜内注射治疗荷瘤小鼠，显著抑制肿瘤细胞生长，降低了肿瘤细胞PCNA蛋白表达[6]。P005091治疗还降低了肿瘤组织中IL-10 mRNA水平，同时升高了IFN-γ和TNF-α的mRNA水平[6]。P005091（10mg/kg）尾静脉注射显著降低了小鼠细胞中MyD88的蛋白水平[7]。