PR-619作為廣譜去泛素化酶抑制劑在線粒體自噬調(diào)控中的應(yīng)用

PR-619（AbMole，M2565）是一種廣譜的去泛素化酶（DUBs）抑制劑，其作用機(jī)制涉及通過(guò)增強(qiáng)蛋白泛素化和誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激（激活I(lǐng)RE1、GRP78、caspase-4、CHOP等）來(lái)調(diào)控細(xì)胞應(yīng)激反應(yīng)，從而抑制細(xì)胞增殖并促進(jìn)凋亡。PR-619在豬卵母細(xì)胞體外成熟實(shí)驗(yàn)的研究（IVM）中，顯著降低成熟率（濃度為10μM和15μM）[1]。PR-619在膀胱尿路上皮癌（UC）細(xì)胞系T24和BFTC-905中，與Cisplatin（順鉑，CDDP）聯(lián)用可增強(qiáng)順鉑的細(xì)胞毒性[2]；PR-619在食管鱗狀細(xì)胞癌（ESCC）細(xì)胞中，通過(guò)激活caspases和PARP裂解誘導(dǎo)G0/G1期細(xì)胞周期阻滯[3]。

PR-619能在動(dòng)物模型中，如BALB/c小鼠結(jié)直腸癌模型中與抗PD1聯(lián)用顯著抑制腫瘤生長(zhǎng)[4]，并在小鼠模型中通過(guò)上調(diào)parkin介導(dǎo)的線粒體自噬（表現(xiàn)為L(zhǎng)C3-II/LC3-I比值升高和LAMP1水平增加）發(fā)揮細(xì)胞（視網(wǎng)膜神經(jīng)節(jié)細(xì)胞）保護(hù)作用[5, 6]。此外，PR-619在Sprague-Dawley大鼠中可減輕腎纖維化，抑制Smad4的表達(dá)[7]，以及在C57BL/6小鼠眼高壓模型中通過(guò)parkin依賴的線粒體自噬途徑保護(hù)視網(wǎng)膜神經(jīng)節(jié)細(xì)胞（RGCs）[6]。研究還顯示，PR-619在10 mg/kg劑量下對(duì)白血病MV4-11細(xì)胞移植瘤小鼠模型表現(xiàn)出顯著的抑制活性[8]。

參考文獻(xiàn)及鳴謝
[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 science 2017, 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. Cells 2019, 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 research 2023, 13 (7), 3055-3066.
[4] Wu, J.; Liu, C.; Wang, T.; et al. Deubiquitinase inhibitor PR-619 potentiates colon cancer immunotherapy by inducing ferroptosis. Immunology 2023, 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 reports 2024, 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. Neuroreport 2020, 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 one 2018, 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 chemistry 2018, 158, 896-916.