AbMole小讲堂丨PR-619：光谱去泛素化酶在内质网应激、凋亡诱导到线粒体自噬调控中的应用

PR-619（AbMole，M2565）是一种广谱的去泛素化酶（DUBs）抑制剂，其作用机制涉及通过增强蛋白泛素化和诱导内质网应激（激活IRE1、GRP78、caspase-4、CHOP等）来调控细胞应激反应，从而抑制细胞增殖并促进凋亡。PR-619在猪卵母细胞体外成熟实验的研究（IVM）中，显著降低成熟率（浓度为10μM和15μM）[1]。PR-619在膀胱尿路上皮癌（UC）细胞系T24和BFTC-905中，与Cisplatin（顺铂，CDDP）联用可增强顺铂的细胞毒性[2]；PR-619在食管鳞状细胞癌（ESCC）细胞中，通过激活caspases和PARP裂解诱导G0/G1期细胞周期阻滞[3]。

PR-619能在动物模型中，如BALB/c小鼠结直肠癌模型中与抗PD1联用显著抑制肿瘤生长[4]，并在小鼠模型中通过上调parkin介导的线粒体自噬（表现为LC3-II/LC3-I比值升高和LAMP1水平增加）发挥细胞（视网膜神经节细胞）保护作用[5, 6]。此外，PR-619在Sprague-Dawley大鼠中可减轻肾纤维化，抑制Smad4的表达[7]，以及在C57BL/6小鼠眼高压模型中通过parkin依赖的线粒体自噬途径保护视网膜神经节细胞（RGCs）[6]。研究还显示，PR-619在10 mg/kg剂量下对白血病MV4-11细胞移植瘤小鼠模型表现出显著的抑制活性[8]。

参考文献及鸣谢

[1] Wang, Y.; Zhuang, L.; Chen, X.; et al. Inhibition of deubiquitinases alters gamete ubiquitination states and sperm-oocyte binding ability in pigs.Animal reproduction science2017,187, 64-73.

[2] Kuo, K. L.; Liu, S. H.; Lin, W. C.; et al. The Deubiquitinating Enzyme Inhibitor PR-619 Enhances the Cytotoxicity of Cisplatin via the Suppression of Anti-Apoptotic Bcl-2 Protein: In Vitro and In Vivo Study.Cells2019,8(10).

[3] Lin, W. C.; Chiu, Y. L.; Kuo, K. L.; et al. Anti-tumor effects of deubiquitinating enzyme inhibitor PR-619 in human chondrosarcoma through reduced cell proliferation and endoplasmic reticulum stress-related apoptosis.American journal of cancer research2023,13(7), 3055-3066.

[4] Wu, J.; Liu, C.; Wang, T.; et al. Deubiquitinase inhibitor PR-619 potentiates colon cancer immunotherapy by inducing ferroptosis.Immunology2023,170(3), 439-451.

[5] Hu, X.; Zhang, J.; Ma, H.; et al. The broad-spectrum deubiquitinating enzyme inhibitor PR-619 protects retinal ganglion cell and augments parkin-mediated mitophagy in experimental glaucoma.Scientific reports2024,14(1), 24654.

[6] Hu, X.; Zhuang, D.; Zhang, R.; et al. The small molecule inhibitor PR-619 protects retinal ganglion cells against glutamate excitotoxicity.Neuroreport2020,31(16), 1134-1141.

[7] Soji, K.; Doi, S.; Nakashima, A.; et al. Deubiquitinase inhibitor PR-619 reduces Smad4 expression and suppresses renal fibrosis in mice with unilateral ureteral obstruction.PloS one2018,13(8), e0202409.

[8] Wang, B.; Wu, J.; Wu, Y.; et al. Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor.European journal of medicinal chemistry2018,158, 896-916