GSK2643943A is a deubiquitinase (DUB) inhibitor targeting USP20. GSK2643943A blocks the cleavage of protein-ubiquitin bonds by inhibiting USP20/Ub-Rho (IC50=160nM)[1-2]. GSK2643943A can be used in research related to cancers such as oral squamous cell carcinoma (OSCC) and T-cell acute lymphoblastic leukemia (T-ALL)[3-4].
In vitro, A549 and NCI-H460 cells were treated with GSK2643943A (160nM) for 24-72 hours. GSK2643943A reduced cytoplasmic PTEN protein levels and increased PTEN ubiquitination. When co-treated with pcDNA3.1-OTUD5, GSK2643943A reversed the inhibitory effects of OTUD5 overexpression on cell proliferation, migration, and invasion[5]. HEK293FT cells were incubated with GSK2643943A (1-5μM) for 12 hours. GSK2643943A led to elevated levels of ubiquitination of the endoplasmic reticulum autophagy receptor RETREG1[6].
In vivo, GSK2643943A (15mg/kg) was administered via intraperitoneal injection once daily for a total of 10 times (5 consecutive days, followed by a 2-day interval, then another 5 consecutive days) to NSG mice inoculated with T-ALL cells. GSK2643943A significantly prolonged the survival of the mice[7]. GSK2643943A (5mg/kg or 2.5mg/kg) was administered via intraperitoneal injection once daily for 6 or 9 consecutive days to mice bearing SCC9 or SCC7 tumors. The combination treatment of GSK2643943A and the oncolytic virus T1012G significantly inhibited tumor growth in mice[8].
References:
[1] Qin B, Zhou L, Wang F, et al. Ubiquitin-specific protease 20 in human disease: Emerging role and therapeutic implications. Biochem Pharmacol. 2022 Dec;206:115352.
[2] Jiang X, Zhao B, Wang T, et al. USP20-Driven Cholesterol Metabolism Links Inflammatory Signaling to Malignancy and Stromal Coevolution in Pancreatic Cancer. Cancer Res. 2026 Feb 2;86(3):712-729.
[3] Li WT, Jin X, Song SJ, et al. Blocking SLC7A11 attenuates the proliferation of esophageal squamous cell carcinoma cells. Anim Cells Syst (Seoul). 2024 May 11;28(1):237-250.
[4] Böhm K, Schulze-Niemand E, Kähne T, et al. Synthesis and structure-activity relationships of USP48 deubiquitinylase inhibitors. Arch Pharm (Weinheim). 2023 Jul;356(7):e2200661.
[5] Li X, Lu B, Zhang L, et al. Mechanism of OTUD5 in non-small cell lung cancer cell proliferation, invasion, and migration. Bosn J Basic Med Sci. 2022 Oct 23;22(6):901-911.
[6] Zhang M, Wang Z, Zhao Q, et al. USP20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B to drive reticulophagy. Autophagy. 2024 Aug;20(8):1780-1797.
[7] Xu L, Zhang Z, Yu J, et al. USP20 as a super-enhancer-regulated gene drives T-ALL progression via HIF1A deubiquitination. Acta Pharm Sin B. 2025 Sep;15(9):4751-4771.
[8] Lu R, Wu G, Chen M, et al. USP18 and USP20 restrict oHSV-1 replication in resistant human oral squamous carcinoma cell line SCC9 and affect the viability of SCC9 cells. Mol Ther Oncolytics. 2021 Nov 11;23:477-487.
GSK2643943A是一种靶向USP20的去泛素化酶（DUB）抑制剂，GSK2643943A通过抑制USP20/Ub-Rho（IC50=160nM）的活性来阻断蛋白质-泛素键的裂解[1-2]。GSK2643943A可用于口腔鳞状细胞癌（OSCC）和T细胞急性淋巴细胞白血病（T-ALL）等癌症的相关研究[3-4]。
在体外，GSK2643943A（160nM）处理A549和NCI-H460细胞24-72小时。GSK2643943A降低了细胞质PTEN的蛋白水平，同时增加了PTEN的泛素化水平；当与pcDNA3.1-OTUD5共处理时，GSK2643943A逆转了OTUD5过表达对细胞增殖、迁移和侵袭的抑制作用[5]。GSK2643943A（1-5μM）孵育HEK293FT细胞12小时。GSK2643943A导致细胞的内质网自噬受体RETREG1泛素化水平升高[6]。
在体内，GSK2643943A（15mg/kg）通过腹腔注射于接种了T-ALL细胞的NSG小鼠，每天给药一次、共计10次（连续注射5天后，时隔2天后再连续注射5天）。GSK2643943A显著延长了小鼠的生存期[7]。GSK2643943A（5mg/kg或2.5mg/kg）通过腹腔注射于携带SCC9或SCC7肿瘤的小鼠，每天给药一次、连续6天或9天。GSK2643943A联合溶瘤病毒T1012G的治疗显著抑制了小鼠的肿瘤生长[8]。