P005091

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.