JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2023
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IF 3.4
Jinhua Li,Namrta Choudhry,Gang Lv,Naganna Nimishetti,Mallu Chenna Reddy,Hong Liu,Thaddeus D. Allen,Jing Zhang,Dun Yang
This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions , such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1 , and AO . Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC 50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development .
研究领域:
药理学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
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2020
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IF 4.831
Min Nie,Yadong Wang,Zenong Yu,Xinyu Li,Yexuan Deng,Ying Wang,Dongjun Yang,Qixiang Li,Xiangwei Zeng,Junyi Ju,Ming Liu,Quan Zhao
Aurora kinase B (AURKB) triggers the phosphorylation of serine 10 on histone H3 (H3S10ph), which is important for chromosome condensation and cytokinesis during mitosis in mammals. However, how exactly AURKB controls cell cycle and contributes to tumorigenesis as an oncoprotein under pathological conditions remains largely unknown. Here, we report that AURKB promotes gastric cancer cell proliferation in vitro and in vivo . Silencing AURKB expression inhibits gastric cell proliferation and arrests the cell cycle in G 2 /M phase. We demonstrate that cyclin D1 (CCND1) is a direct downstream target of AURKB that plays a key role in gastric cancer cell proliferation. AURKB is able to activate the expression of CCND1 through mediating H3S10ph in the promoter of the CCND1 gene. Furthermore, we show that AZD1152, a specific inhibitor of AURKB, can suppress the expression of CCND1 in the gastric cancer cells and inhibit cell proliferation in vitro and in vivo . Importantly, we found that high AURKB and CCND1 expression levels are correlated with shorter overall survival of gastric cancer patients. This study demonstrates that AURKB promotes gastric tumorigenesis potentially through epigenetically activating CCND1 expression, suggesting AURKB as a promising therapeutic target in gastric cancer.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
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2026
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IF 13.6
Tang Tianyu,Yang Wuping,Lu Minghao,Peng Ding,Li Shiqi,Cui Sijia,Ye Sunyi,Liu Jiandong,Wang Yifan,Wu Cunjin,Teng Haoyang,Huang Haojie,Xu Xin,Xia Dan,Zhu Yi
Aberrant tumor metabolism plays a crucial role in establishing and sustaining an immunosuppressive microenvironment. CD73, a key enzyme in the purine metabolism pathway, is frequently overexpressed in tumors, leading to elevated extracellular adenosine (ADO) levels. This accumulation suppresses antitumor immune responses by promoting immune cell exhaustion, ultimately contributing to immunotherapy resistance. However, the mechanisms underlying CD73 upregulation in tumors remain poorly defined. Here, we identify aurora kinase B (AURKB) as a critical regulator of CD73 overexpression in renal cell carcinoma (RCC), orchestrating immune evasion and resistance to immune checkpoint therapy. AURKB is highly expressed in RCC, with its prognostic significance being especially evident in tumors with strong immunogenicity. Mechanistically, AURKB enhances CD73 expression, thereby promoting T cell dysfunction and immune suppression. Mass cytometry (CyTOF) analysis revealed that AURKB inhibition facilitates immune infiltration and alleviates immune exhaustion. We further demonstrate that AURKB directly interacts with CD73 and phosphorylates it at serine 429, which inhibits STUB1-mediated ubiquitination and proteasomal degradation of CD73. Targeting AURKB to modulate the post-translational stability of CD73 restores antitumor immunity and synergizes with immune checkpoint blockade in vivo. Collectively, this study uncovers a previously unrecognized AURKB–CD73 axis and provides a mechanistically informed strategy to enhance immunotherapy efficacy in RCC.
✓ 已验证
产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2022
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IF 7.419
Ziqi Yan,Qiong Shi,Xumei Liu,Jinhua Li,Vidhula Ahire,Shenqiu Zhang,Jing Zhang,Dun Yang,Thaddeus D. Allen
Plants are a rich source for bioactive compounds. However, plant extracts can harbor a mixture of bioactive molecules that promote divergent phenotypes and potentially have confounding effects in bioassays. Even with further purification and identification, target deconvolution can be challenging. Corynoline and acetylcorynoline, are phytochemicals that were previously isolated through a screen for compounds able to induce mitotic arrest and polyploidy in oncogene expressing retinal pigment epithelial (RPE) cells. Here, we shed light on the mechanism by which these phytochemicals can attack human cancer cells. Mitotic arrest was coincident to the induction of centrosome amplification and declustering, causing multi-polar spindle formation. Corynoline was demonstrated to have true centrosome declustering activity in a model where A549 cells were chemically induced to have more than a regular complement of centrosomes. Corynoline could inhibit the centrosome clustering required for pseudo-bipolar spindle formation in these cells. The activity of AURKB, but not AURKA or polo-like kinase 4, was diminished by corynoline. It only partially inhibited AURKB, so it may be a partial antagonist or corynoline may work upstream on an unknown regulator of AURKB activity or localization. Nonetheless, corynoline and acetylcorynoline inhibited the viability of a variety of human cancer derived cell lines. These phytochemicals could serve as prototypes for a next-generation analog with improved potency, selectivity or in vivo bioavailability. Such an analog could be useful as a non-toxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.
研究领域:
药理学
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癌症生物学
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细胞生物学
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植物科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Chemical Biology
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2024
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IF 6.6
KeJing Zhang,Juan Wei,SheYu Zhang,Liyan Fei,Lu Guo,Xueying Liu,YiShuai Ji,WenJun Chen,Felipe E. Ciamponi,WeiChang Chen,MengXi Li,Jie Zhai,Ting Fu,Katlin B. Massirer,Yang Yu,Mathieu Lupien,Yong Wei,Cheryl. H. Arrowsmith,Qin Wu,WeiHong Tan
Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）