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1
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Chen Y, Dong H, Huang X, Jiang L, Jiang Z, Li L, Hu J, Chen WH. Discovery of fluorescent and theranostic probes for glycogen synthase kinase-3β in living cells and brain tissues: Detection and imaging in models of Alzheimer's disease. Eur J Med Chem 2025; 291:117639. [PMID: 40267876 DOI: 10.1016/j.ejmech.2025.117639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/31/2025] [Accepted: 04/14/2025] [Indexed: 04/25/2025]
Abstract
Alzheimer's disease (AD) represents a progressive neurodegenerative disorder marked by complex pathologies. Glycogen synthase kinase-3β (GSK-3β) plays a pivotal role in AD pathogenesis, influencing key pathological processes such as hyperphosphorylation of tau and production of amyloid-beta. However, current methods for detecting GSK-3β in living cells and tissues are limited in sensitivity and real-time tracking. Herein, we reported a series of environment-sensitive fluorescent probes to detect GSK-3β in both living cells and brain slices. These probes exhibit fluorescence upon the binding of GSK-3β, providing high sensitivity and selectivity with minimal background interference. Compound 10c was further validated in an AD mouse model with elevated expression of GSK-3β, showing clear imaging in hippocampal regions. Compared to immunofluorescence, compound 10c demonstrated a lower background and faster labeling. In addition, this compound showed neuroprotective effects, supporting its potential as a theranostic tool in AD. These findings provide new tools for investigating the role of GSK-3β in AD and advancing targeted therapies.
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Affiliation(s)
- Yu Chen
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China
| | - Hanyue Dong
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China
| | - Xiaoling Huang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China
| | - Lulu Jiang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China
| | - Zixing Jiang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China
| | - Lanqing Li
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China
| | - Jinhui Hu
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China.
| | - Wen-Hua Chen
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China.
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2
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Wu Q, Hou Q, Wang P, Ding C, Lv S. Antifouling Electrochemiluminescence Biosensor Based on Bovine Serum Albumin Hydrogel for the Accurate Detection of p53 Gene in Human Serum. ACS APPLIED MATERIALS & INTERFACES 2023; 15:44322-44330. [PMID: 37672622 DOI: 10.1021/acsami.3c09737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
To detect biomarkers in complex samples, it is fundamental to avoid the nonspecific adsorption of impurities to improve the selectivity of biosensors. In this study, a sensitive antifouling electrochemiluminescence biosensor was proposed based on bovine serum albumin (BSA)- and exonuclease III (Exo III)-mediated nucleic acid cycle signal amplification strategy. Ti3C2Tx-NH4, which has a large surface area and high metal conductivity, was crosslinked with BSA to improve the conductivity of the sensing interface, which shows antifouling performance excellently due to the electrical neutrality and good hydrophilicity of BSA hydrogel. The cyclic amplification strategy based on Exo III and DNA hybridization chain reaction significantly amplified the electrochemiluminescence signal and improved the sensitivity of p53 gene detection. The linear range of the biosensor is 1 fM-1 nM with a detection limit of 0.26 fM. More importantly, the sensor showed excellent selectivity when it was used to detect the p53 gene in real samples, such as serum. Thus, this unique antifouling sensing interface is expected to construct various electrochemical biosensors in clinical diagnosis and biopathological analysis.
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Affiliation(s)
- Qiongwei Wu
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, Ministry of Education; Shandong Key Laboratory of Biochemical Analysis; Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong; College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China
| | - Qianqian Hou
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, Ministry of Education; Shandong Key Laboratory of Biochemical Analysis; Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong; College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China
| | - Peipei Wang
- Department of Rehabilitation Medicine, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao 266042, China
| | - Caifeng Ding
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, Ministry of Education; Shandong Key Laboratory of Biochemical Analysis; Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong; College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China
- Department of Rehabilitation Medicine, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao 266042, China
| | - Shaoping Lv
- Department of Rehabilitation Medicine, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao 266042, China
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3
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Li K, Wu S, Dong G, Li Y, Wang W, Dong G, Hong Z, Li M, Sheng C. Environmentally sensitive fluorescent probes with improved properties for detecting and imaging PDEδ in live cells and tumor slices. CHINESE CHEM LETT 2023. [DOI: 10.1016/j.cclet.2023.108231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
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4
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Miles X, Vandevoorde C, Hunter A, Bolcaen J. MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy. Front Oncol 2021; 11:703442. [PMID: 34307171 PMCID: PMC8296304 DOI: 10.3389/fonc.2021.703442] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reactivating p53 is suggested as a treatment strategy, either by using targeted molecules to convert the mutant p53 back to its wild type form or by using MDM2 and MDMX (also known as MDM4) inhibitors. MDM2 down regulates p53 activity via ubiquitin-dependent degradation and is amplified or overexpressed in 14% of GB cases. Thus, suppression of MDM2 offers an opportunity for urgently needed new therapeutic interventions for GB. Numerous small molecule MDM2 inhibitors are currently undergoing clinical evaluation, either as monotherapy or in combination with chemotherapy and/or other targeted agents. In addition, considering the major role of both p53 and MDM2 in the downstream signaling response to radiation-induced DNA damage, the combination of MDM2 inhibitors with radiation may offer a valuable therapeutic radiosensitizing approach for GB therapy. This review covers the role of MDM2/X in cancer and more specifically in GB, followed by the rationale for the potential radiosensitizing effect of MDM2 inhibition. Finally, the current status of MDM2/X inhibition and p53 activation for the treatment of GB is given.
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Affiliation(s)
- Xanthene Miles
- Radiobiology, Radiation Biophysics Division, Nuclear Medicine Department, iThemba LABS, Cape Town, South Africa
| | - Charlot Vandevoorde
- Radiobiology, Radiation Biophysics Division, Nuclear Medicine Department, iThemba LABS, Cape Town, South Africa
| | - Alistair Hunter
- Radiobiology Section, Division of Radiation Oncology, Department of Radiation Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Julie Bolcaen
- Radiobiology, Radiation Biophysics Division, Nuclear Medicine Department, iThemba LABS, Cape Town, South Africa
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5
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Dong G, Chen L, Zhang J, Liu T, Du L, Sheng C, Li M. Discovery of Turn-On Fluorescent Probes for Detecting PDEδ Protein in Living Cells and Tumor Slices. Anal Chem 2020; 92:9516-9522. [PMID: 32571022 DOI: 10.1021/acs.analchem.0c00335] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The first small-molecule fluorescent turn-on probes for detecting PDEδ protein were rationally designed, showing reasonable fluorescent properties and the fluorescent ability has been applied for visualization of the PDEδ protein in living cells and at tissue levels. The qPCR results showed that the mRNA expression of KRAS, PDEδ, AKT1, MAPK1, MEK7, RAF1, and mTOR were downregulated by probes 1-3 through PI3K/AKT/mTOR and MAPK signal pathways. The probes also can downregulate the protein level of pErk and tErk. Therefore, these small-molecule fluorescent probes are expected to be used in the screening of antipancreatic cancer drugs targeting the PDEδ protein, as well as in obtaining a better understanding of the pathological and physiological roles of PDEδ protein.
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Affiliation(s)
- Gaopan Dong
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Long Chen
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Jing Zhang
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Tingting Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.,Institute of Pharmacology, School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271000, China
| | - Lupei Du
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Chunquan Sheng
- Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Minyong Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
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6
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Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm Sin B 2020; 10:1253-1278. [PMID: 32874827 PMCID: PMC7452049 DOI: 10.1016/j.apsb.2020.01.003] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/31/2019] [Accepted: 12/26/2019] [Indexed: 12/26/2022] Open
Abstract
Blocking the MDM2/X–P53 protein–protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2–P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure–activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.
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7
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Liu P, Fu W, Verwilst P, Won M, Shin J, Cai Z, Tong B, Shi J, Dong Y, Kim JS. MDM2‐Associated Clusterization‐Triggered Emission and Apoptosis Induction Effectuated by a Theranostic Spiropolymer. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.201916524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Pai Liu
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications School of Materials Science and Engineering Beijing Institute of Technology Beijing 100081 China
- Department of Chemistry Korea University Seoul 02841 Korea
| | - Weiqiang Fu
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications School of Materials Science and Engineering Beijing Institute of Technology Beijing 100081 China
| | - Peter Verwilst
- Department of Chemistry Korea University Seoul 02841 Korea
- Current address: KU Leuven Rega Institute of Medical Research Medicinal Chemistry 3000 Leuven Belgium
| | - Miae Won
- Department of Chemistry Korea University Seoul 02841 Korea
| | - Jinwoo Shin
- Department of Chemistry Korea University Seoul 02841 Korea
| | - Zhengxu Cai
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications School of Materials Science and Engineering Beijing Institute of Technology Beijing 100081 China
| | - Bin Tong
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications School of Materials Science and Engineering Beijing Institute of Technology Beijing 100081 China
| | - Jianbing Shi
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications School of Materials Science and Engineering Beijing Institute of Technology Beijing 100081 China
| | - Yuping Dong
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications School of Materials Science and Engineering Beijing Institute of Technology Beijing 100081 China
| | - Jong Seung Kim
- Department of Chemistry Korea University Seoul 02841 Korea
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8
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Liu P, Fu W, Verwilst P, Won M, Shin J, Cai Z, Tong B, Shi J, Dong Y, Kim JS. MDM2-Associated Clusterization-Triggered Emission and Apoptosis Induction Effectuated by a Theranostic Spiropolymer. Angew Chem Int Ed Engl 2020; 59:8435-8439. [PMID: 32052897 DOI: 10.1002/anie.201916524] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Indexed: 01/15/2023]
Abstract
Heteroatom-containing spiropolymers were constructed in a facile manner by a catalyst-free multicomponent spiropolymerization route. P1a2b as the most potent of these spiropolymers, demonstrates cluster-triggered emission resulting from strong interactions with the MDM2 protein. By preventing the anti-apoptotic p53/MDM2 interaction, P1a2b triggers apoptosis in cancerous cells, while demonstrating a good biocompatibility and non-toxicity in non-cancerous cells. The combined results from solution and cell-based cluster-triggered emission studies, docking, protein expression experiments and cytotoxicity data strongly support the MDM2-binding hypothesis and indicate a potential application as a fluorescent cancer marker as well as therapeutic for this spiropolymer.
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Affiliation(s)
- Pai Liu
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, 100081, China
- Department of Chemistry, Korea University, Seoul, 02841, Korea
| | - Weiqiang Fu
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Peter Verwilst
- Department of Chemistry, Korea University, Seoul, 02841, Korea
- Current address: KU Leuven, Rega Institute of Medical Research, Medicinal Chemistry, 3000, Leuven, Belgium
| | - Miae Won
- Department of Chemistry, Korea University, Seoul, 02841, Korea
| | - Jinwoo Shin
- Department of Chemistry, Korea University, Seoul, 02841, Korea
| | - Zhengxu Cai
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Bin Tong
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Jianbing Shi
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Yuping Dong
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, 100081, China
| | - Jong Seung Kim
- Department of Chemistry, Korea University, Seoul, 02841, Korea
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9
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Dong G, He S, Qin X, Liu T, Jiang Y, Li X, Chen L, Han G, Sheng C, Li M. Discovery of Nonpeptide, Environmentally Sensitive Fluorescent Probes for Imaging p53-MDM2 Interactions in Living Cell Lines and Tissue Slice. Anal Chem 2020; 92:2642-2648. [PMID: 31918545 DOI: 10.1021/acs.analchem.9b04551] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Based on structural optimization work, probes 9-11 with practical activity and selectivity in tissue as well as living cell lines are well designed and synthesized. All the probes showed potent inhibitory and acceptable cell toxicity compared with the commercially available p53-MDM2 inhibitor Nutlin-3, and can increase the protein expression level of p53 and MDM2 in the A549 cell line; in particular, probes 10 and 11 can increase the protein expression level of p53 better than Nutlin-3. Moreover, their application in imaging and detecting wild-type p53-MDM2 protein-protein interactions have been well demonstrated in at the cell and tissue levels. Overall, these environmentally sensitive fluorescent turn-on probes are affordable and rapid for imaging, which is expected for applications in target drug screening as well as in pathologic diagnosis.
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Affiliation(s)
- Gaopan Dong
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China
| | - Shipeng He
- Department of Medicinal Chemistry, School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China
| | - Xiaojun Qin
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China
| | - Tingting Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China.,Institute of Pharmacology, School of Pharmaceutical Sciences , Shandong First Medical University & Shandong Academy of Medical Sciences , Taian 271000 , Shandong China
| | - Yan Jiang
- Department of Medicinal Chemistry, School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China
| | - Xiang Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China
| | - Long Chen
- Department of Medicinal Chemistry, School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China
| | - Guangxi Han
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China
| | - Chunquan Sheng
- Department of Medicinal Chemistry, School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China
| | - Minyong Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China
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10
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Liu T, Dong G, Xu F, Han B, Fang H, Huang Y, Zhou Y, Du L, Li M. Discovery of Turn-On Fluorescent Probes for Detecting Bcl-2 Protein. Anal Chem 2019; 91:5722-5728. [DOI: 10.1021/acs.analchem.8b05853] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Tingting Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Gaopan Dong
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Feng Xu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Bo Han
- Department of Pathology, School of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Hao Fang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Yun Huang
- Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77030, United States
| | - Yubin Zhou
- Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77030, United States
| | - Lupei Du
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Minyong Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, China
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11
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Lebraud H, Noble RA, Phillips N, Heam K, Castro J, Zhao Y, Newell DR, Lunec J, Wedge SR, Heightman TD. Highly Potent Clickable Probe for Cellular Imaging of MDM2 and Assessing Dynamic Responses to MDM2-p53 Inhibition. Bioconjug Chem 2018; 29:2100-2106. [PMID: 29851469 DOI: 10.1021/acs.bioconjchem.8b00315] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding of MDM2 to p53 represses the protein's transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function in TP53 wild-type tumors. Here, we describe the design, synthesis, and biological evaluation of a trans-cyclooctene tagged derivative of RG7388, RG7388-TCO, which showed high cellular potency and specificity for MDM2. The in-cell reaction of RG7388-TCO with a tetrazine-tagged BODIPY dye enabled fluorescence imaging of endogenous MDM2 in SJSA-1 and T778 tumor cells. RG7388-TCO was also used to pull down MDM2 by reaction with tetrazine-tagged agarose beads in SJSA-1 lysates. The data presented show that RG733-TCO enables precise imaging of MDM2 in cells and can permit a relative assessment of target engagement and MDM2-p53 antagonism in vitro.
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Affiliation(s)
- Honorine Lebraud
- Astex Pharmaceuticals , 436 Cambridge Science Park , Cambridge CB4 0QA , United Kingdom
| | - Richard A Noble
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School , Newcastle University , Framlington Place , Newcastle-upon-Tyne NE2 4HH , United Kingdom
| | - Nicole Phillips
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School , Newcastle University , Framlington Place , Newcastle-upon-Tyne NE2 4HH , United Kingdom
| | - Keisha Heam
- Astex Pharmaceuticals , 436 Cambridge Science Park , Cambridge CB4 0QA , United Kingdom
| | - Juan Castro
- Astex Pharmaceuticals , 436 Cambridge Science Park , Cambridge CB4 0QA , United Kingdom
| | - Yan Zhao
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School , Newcastle University , Framlington Place , Newcastle-upon-Tyne NE2 4HH , United Kingdom
| | - David R Newell
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School , Newcastle University , Framlington Place , Newcastle-upon-Tyne NE2 4HH , United Kingdom
| | - John Lunec
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School , Newcastle University , Framlington Place , Newcastle-upon-Tyne NE2 4HH , United Kingdom
| | - Stephen R Wedge
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School , Newcastle University , Framlington Place , Newcastle-upon-Tyne NE2 4HH , United Kingdom
| | - Tom D Heightman
- Astex Pharmaceuticals , 436 Cambridge Science Park , Cambridge CB4 0QA , United Kingdom
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12
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Liu T, Gao Y, Zhang X, Wan Y, Du L, Fang H, Li M. Discovery of a Turn-On Fluorescent Probe for Myeloid Cell Leukemia-1 Protein. Anal Chem 2017; 89:11173-11177. [DOI: 10.1021/acs.analchem.7b01148] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Tingting Liu
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Yuqi Gao
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Xiaomeng Zhang
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Yichao Wan
- Key
Laboratory of Theoretical Organic Chemistry and Functional Molecule
(MOE), College of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
| | - Lupei Du
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Hao Fang
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Minyong Li
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
- State
Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, China
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13
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Liu T, Jiang Y, Liu Z, Li J, Fang K, Zhuang C, Du L, Fang H, Sheng C, Li M. Environment-sensitive turn-on fluorescent probes for p53-MDM2 protein-protein interaction. MEDCHEMCOMM 2017; 8:1668-1672. [PMID: 30108877 DOI: 10.1039/c7md00287d] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 06/30/2017] [Indexed: 12/12/2022]
Abstract
A series of probes with a turn-on switch for the p53-MDM2 protein-protein interaction were developed. After careful evaluation, these small molecule fluorescent probes exhibited high practical activity and selectivity in vitro and in cellulo. In particular probe 10, which had a Ki value of 0.03 μM, displayed much better binding affinity compared to the positive control Nutlin-3, which had a Ki value of 0.23 μM. These no-wash environment-sensitive turn-on fluorescent probes have been successfully applied to imaging p53-MDM2 interaction in the human lung cancer cell line A549 (wild-type p53) at the micromolar level. Therefore, these fluorescent probes are expected to be used in drug screening and cell staining in p53-MDM2 fields, as well as in pathological and physiological studies of the p53-MDM2 interaction.
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Affiliation(s)
- Tingting Liu
- Department of Medicinal Chemistry , Key Laboratory of Chemical Biology (MOE) , School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China .
| | - Yan Jiang
- Department of Medicinal Chemistry , School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China .
| | - Zhenzhen Liu
- Department of Medicinal Chemistry , Key Laboratory of Chemical Biology (MOE) , School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China .
| | - Jin Li
- Department of Medicinal Chemistry , School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China .
| | - Kun Fang
- Department of Medicinal Chemistry , School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China .
| | - Chunlin Zhuang
- Department of Medicinal Chemistry , School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China .
| | - Lupei Du
- Department of Medicinal Chemistry , Key Laboratory of Chemical Biology (MOE) , School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China .
| | - Hao Fang
- Department of Medicinal Chemistry , Key Laboratory of Chemical Biology (MOE) , School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China .
| | - Chunquan Sheng
- Department of Medicinal Chemistry , School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China .
| | - Minyong Li
- Department of Medicinal Chemistry , Key Laboratory of Chemical Biology (MOE) , School of Pharmacy , Shandong University , Jinan , Shandong 250012 , China .
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14
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Liu Z, Jiang T, Wang B, Ke B, Zhou Y, Du L, Li M. Environment-Sensitive Fluorescent Probe for the Human Ether-a-go-go-Related Gene Potassium Channel. Anal Chem 2016; 88:1511-5. [PMID: 26730746 PMCID: PMC4741275 DOI: 10.1021/acs.analchem.5b04220] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
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A novel
environment-sensitive probe S2 with turn-on switch for
Human Ether-a-go-go-Related Gene (hERG) potassium channel was developed
herein. After careful evaluation, this fluorescent probe showed high
binding affinity with hERG potassium channel with an IC50 value of 41.65 nM and can be well applied to hERG channel imaging
or cellular distribution study for hERG channel blockers. Compared
with other imaging techniques, such as immunofluorescence and fluorescent
protein-based approaches, this method is convenient and affordable,
especially since a washing procedure is not needed. Meanwhile, this
environment-sensitive turn-on design strategy may provide a good example
for the probe development for these targets that have no reactive
or catalytic activity.
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Affiliation(s)
- Zhenzhen Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China
| | - Tianyu Jiang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China
| | - Beilei Wang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China
| | - Bowen Ke
- Laboratory of Anaesthesiology and Critical Care Medicine, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China
| | - Yubin Zhou
- Institute of Biosciences and Technology, Texas A&M University Health Science Center , Houston, Texas 77030, United States
| | - Lupei Du
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China
| | - Minyong Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China
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15
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Zhou R, Wu Q, Guo M, Huang W, He X, Yang L, Peng F, He G, Han B. Organocatalytic cascade reaction for the asymmetric synthesis of novel chroman-fused spirooxindoles that potently inhibit cancer cell proliferation. Chem Commun (Camb) 2015; 51:13113-6. [PMID: 26186061 DOI: 10.1039/c5cc04968g] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The enantioselective preparation of bioactive chroman-fused spirooxindoles is described. Compound 7e induced apoptosis and cell cycle arrest in MCF-7 cells by interfering with the p53–MDM2 interaction.
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Affiliation(s)
- Rui Zhou
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
| | - Qinjie Wu
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
| | - Mingrui Guo
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
| | - Wei Huang
- State Key Laboratory Breeding Base of Systematic Research
- Development and Utilization of Chinese Medicine Resources
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
| | - Xianghong He
- State Key Laboratory Breeding Base of Systematic Research
- Development and Utilization of Chinese Medicine Resources
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
| | - Lei Yang
- State Key Laboratory Breeding Base of Systematic Research
- Development and Utilization of Chinese Medicine Resources
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
| | - Fu Peng
- School of Chinese Medicine
- University of Hong Kong
- Hong Kong
- China
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
| | - Bo Han
- State Key Laboratory Breeding Base of Systematic Research
- Development and Utilization of Chinese Medicine Resources
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
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