Article
Chemistry, Medicinal
Shuai Wang, Fen-Er Chen
Summary: Inhibition of the MDM2-p53 protein-protein interaction using small-molecule inhibitors is a promising strategy for cancer therapy. Many highly potent and selective small-molecule MDM2 inhibitors have been discovered and are currently undergoing different clinical trials. This review provides an overview of the function of MDM2 and the identification, optimization, preclinical, and clinical studies of clinical-stage MDM2 inhibitors. It also discusses challenges, potential toxicity, and future perspectives, which will guide the design of new small-molecule MDM2 inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Mehregan Babamohamadi, Esmaeil Babaei, Burhan Ahmed Salih, Mahshid Babamohammadi, Hewa Jalal Azeez, Goran Othman
Summary: The p53 protein is a tumor suppressor that regulates various cellular processes and is closely related to cancer development. It can be used as a biomarker for tumor progression and a target for cancer treatment. This review discusses the contribution of wild-type p53 loss of function, its role in ferroptosis and targeted therapy, and challenges and solutions in p53-related drug delivery systems.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Dongjuan Si, Huijuan Luo, Xiaomeng Zhang, Kundi Yang, Hongmei Wen, Wei Li, Jian Liu
Summary: Inhibition of p53-MDM2 interactions is a promising strategy for cancer treatment. The unsaturated pyrrolidone compound 4h showed good binding affinity with MDM2 and demonstrated excellent antitumor activity by inducing cell cycle arrest and apoptosis. This compound has potential as a novel antitumor agent.
BIOORGANIC CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Bin Song, Jiajian Wang, Yixin Ren, Yongnan Su, Xueye Geng, Fan Yang, Hao Wang, Jihong Zhang
Summary: p53 is a transcription factor that activates gene expression for genomic stability, but many cancers have mutations in p53 that render it inactive. Butein, a small molecule, has been identified as a potential drug that can reactivate mutant p53 and restore its tumor-suppressing function. Through various mechanisms, Butein restores the DNA-binding ability of mutant p53, activates p53 target genes, and stabilizes both wild-type and mutant p53 proteins. This study suggests that Butein could be a promising therapeutic agent for cancers with specific p53 mutations.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Oncology
Atif Zafar, Wei Wang, Gang Liu, Wa Xian, Frank McKeon, Jia Zhou, Ruiwen Zhang
Summary: Neuroblastoma poses a significant challenge in pediatric oncology, with p53 protein playing a key protective role against genome instability. Overexpression of MDM2 in neuroblastoma can lead to p53 inhibition, drug resistance, and other non-canonical p53 functions. Research is focused on restoring p53 function by targeting the p53-MDM2 axis for potential therapeutic strategies.
Review
Oncology
Jiahao Hu, Jiasheng Cao, Win Topatana, Sarun Juengpanich, Shijie Li, Bin Zhang, Jiliang Shen, Liuxin Cai, Xiujun Cai, Mingyu Chen
Summary: TP53 is a critical tumor-suppressor gene commonly mutated in human cancers, with potential oncogenic properties when mutated. Treatments for cancers with mutant p53 involve targeting mutant p53 directly, restoring wild-type functions, and exploring synthetic lethal interactions with mutant p53 for therapeutic benefits. Additionally, disrupting noncoding RNA networks may have potential synthetic lethal effects in cancers with p53 mutations.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Shengliang Zhang, Lindsey Carlsen, Liz Hernandez Borrero, Attila A. Seyhan, Xiaobing Tian, Wafik S. El-Deiry
Summary: This article summarizes the current progress in targeting wild-type and mutant p53 for cancer therapy using biotherapeutic and biopharmaceutical methods. Strategies include boosting p53 activity, restoring p53 pathway function, targeting p53 in immunotherapy, and combination therapies.
Article
Biochemistry & Molecular Biology
Assem Barakat, Saeed Alshahrani, Abdullah Mohammed Al-Majid, Abdullah Saleh Alamary, Matti Haukka, Marwa M. Abu-Serie, Alexander Domling, Eman A. Mazyed, Farid A. Badria, Fardous F. El-Senduny
Summary: This study investigated the anticancer activity of the compound SP1 and its nanoformulation against breast adenocarcinoma. The results showed that SP1 exhibited strong inhibitory effects on multiple cancer cell lines and induced apoptosis. The use of a nanoformulation improved the selectivity of the compound against cancer cells. In vivo studies on mice confirmed the ability of SP1 to halt the proliferation of breast cancer cells and suppress metastasis.
BIOORGANIC CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Essam Nageh Sholkamy, Assem Barakat, Maurizio Viale, Paola Menichini, Andrea Speciale, Fabrizio Loiacono, Mohammad Azam, Ved Prakash Verma, Sammer Yousuf, Mohamed Teleb
Summary: Recently, clinical-stage spirooxindole-based MDM2 inhibitors have been introduced in cancer research protocols, but tumor resistance to the treatment has been reported. Therefore, researchers have focused on designing various combinatorial libraries of spirooxindoles. In this study, a new series of spirooxindoles were created through the hybridization of a chemically stable core and a pyrazole motif, inspired by lead pyrazole-based p53 activators and promising molecules previously reported. The derivatives were tested for cytotoxic activities on cancer cell lines and some showed potentiation of doxorubicin activity.
SCIENTIFIC REPORTS
(2023)
Article
Oncology
Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry
Summary: This study identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for mutant p53 degradation in cancer cells, which can be targeted by small-molecule compounds for cancer therapy.
MOLECULAR CANCER RESEARCH
(2022)
Review
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Fatemeh Emadi, Jimma Lenjisa, Laychiluh Mekonnen, Shudong Wang
Summary: As the fifth pillar of cancer treatment, immunotherapy has revolutionized therapeutic strategies by focusing on the host's immune system. The discovery of immune-modulatory effects for kinase inhibitors has opened up new possibilities in this approach, as these small molecule inhibitors not only directly target essential proteins for tumor survival and proliferation, but also stimulate immune responses against malignant cells.
DRUG DISCOVERY TODAY
(2023)
Review
Cell Biology
Alyssa M. Klein, Rafaela Muniz de Queiroz, Divya Venkatesh, Carol Prives
Summary: MDM2 and MDMX, well-known as proteins that restrain the p53 tumor suppressor protein, have diverse functions in cells and are regulated at multiple levels including transcription and protein modification. Both proteins may contribute to oncogenic transformation while also potentially playing a tumor suppressive role in certain contexts. Understanding how various small molecules affecting MDM2 and MDMX may impact their p53-independent activities is crucial due to their therapeutic potential.
GENES & DEVELOPMENT
(2021)
Article
Oncology
Min Lu, Lijuan Xia, Nada Elmansy, Cara Clementelli, Douglas Tremblay, Ronald Hoffman
Summary: Combination treatment with ONC201 and RG7112 effectively promotes apoptosis of MF CD34(+) cells through activation of both p53-dependent and -independent pathways. This treatment not only decreases the number of mutated colonies but also allows for the persistence or appearance of wild type colonies, potentially providing an effective strategy for treating MF patients.
Article
Biochemistry & Molecular Biology
Gehad Lotfy, Yasmine M. Abdel Aziz, Mohamed M. Said, El Sayed H. El Ashry, El Sayed H. El Tamany, Marwa M. Abu-Serie, Mohamed Teleb, Alexander Domling, Assem Barakat
Summary: Combination of MDM2 and BCL2 inhibition can sensitize tumor cells and induce apoptosis synergistically. Novel MDM2 inhibitors 5i and 5q showed promising anticancer activities and apoptosis induction effects in cancer cells in vitro tests.
BIOORGANIC CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Delin Chen, Bo Chu, Xin Yang, Zhaoqi Liu, Ying Jin, Ning Kon, Raul Rabadan, Xuejun Jiang, Brent R. Stockwell, Wei Gu
Summary: The study identifies iPLA2 beta as a critical regulator for p53-driven ferroptosis independent of GPX4. Loss of iPLA2 beta does not have obvious effect on normal cells, but it plays an essential role in regulating ferroptosis upon ROS-induced stress. iPLA2 beta is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.
NATURE COMMUNICATIONS
(2021)
Editorial Material
Pharmacology & Pharmacy
Songtao Li, Zhenyuan Song, Ping Yao, Jiangjiang Qin
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Xuan Hong, Xiaoqing Guan, Qiliang Lai, Dehua Yu, Zhongwei Chen, Xiaoteng Fu, Beibei Zhang, Changkun Chen, Zongze Shao, Jinmei Xia, Jiang-Jiang Qin, Weiyi Wang
Summary: A new meroterpenoid, taladrimanin A (1), was isolated from a marine-derived fungus, and its structure and activity were studied. Compound 1 showed inhibitory activity against gastric cancer cells and certain bacteria.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Simin Qi, Xiaoqing Guan, Jia Zhang, Dehua Yu, Xuefei Yu, Qinglin Li, Wenjuan Yin, Xiang-Dong Cheng, Weidong Zhang, Jiang-Jiang Qin
Summary: Inhibiting UbcH5c has been identified as a novel and effective strategy for treating pancreatic cancer, and DHPO represents a new class of UbcH5c inhibitor with potential as an anti-pancreatic cancer therapeutic agent.
Article
Pharmacology & Pharmacy
Jing-Li Xu, Li Yuan, Can Hu, Chun-Yan Weng, Han-Dong Xu, Yun-Fu Shi, Ling Huang, Jie-Er Ying, Zhi-Yuan Xu, Jiang-Jiang Qin, Xiang-Dong Cheng
Summary: The combination of TRM extract (TRMBE) and 5-FU can enhance the anticancer activity of 5-FU, prolong the survival time of mice bearing MFC xenograft tumors, and reduce the risk of liver metastasis in gastric cancer. This combination therapy also modulates immune cytokines, reshapes the tumor microenvironment, and improves the therapeutic effects of 5-FU.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Dehua Yu, Simin Qi, Xiaoqing Guan, Wenkai Yu, Xuefei Yu, Maohua Cai, Qinglin Li, Weiyi Wang, Weidong Zhang, Jiang-Jiang Qin
Summary: In this study, the marine-derived natural product terphenyllin was identified to directly interact with STAT3 and exhibit potent anticancer efficacy against gastric cancer through inhibiting the STAT3 signaling pathway.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Xuefei Yu, Xuhang Zhu, Lizhuo Zhang, Jiang-Jiang Qin, Chunlai Feng, Qinglin Li
Summary: This study confirmed the association between PDGFRA and radioiodine resistance in thyroid cancer and developed a prediction model of PDGFRA inhibitors using bioinformatics analysis, machine learning, and molecular docking. A potential PDGFRA inhibitor was identified from a traditional Chinese medicine compound library, which showed significant inhibitory effects on PDGFRA-MAPK pathway activation and improved radioiodine uptake capacity in radioiodine-refractory thyroid cancer.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Oncology
Li Yuan, Jingli Xu, Yunfu Shi, Zhiyuan Jin, Zhehan Bao, Pengcheng Yu, Yi Wang, Yuhang Xia, Jiangjiang Qin, Bo Zhang, Qinghua Yao
Summary: The study found that CD3D protein is highly expressed in gastric cancer tissues and is associated with prognosis and factors such as tumor infiltrating lymphocytes. CD3D may play an important regulatory role in the tumor immune microenvironment of gastric cancer and could potentially serve as a marker for prognosis and immunotherapy response.
FRONTIERS IN ONCOLOGY
(2022)
Review
Oncology
Fei Cao, Can Hu, Zhi-Yuan Xu, Yan-Qiang Zhang, Ling Huang, Jia-Hui Chen, Jiang-Jiang Qin, Xiang-Dong Cheng
Summary: This article introduces the existing treatments for adenocarcinoma of the esophagogastric junction (AEG), including surgical therapy, neoadjuvant therapy, and targeted therapy, and forecasts future research directions.
ANNALS OF TRANSLATIONAL MEDICINE
(2022)
Editorial Material
Biochemistry & Molecular Biology
Jian-ye Zhang, Jiang-Jiang Qin, Dongmei Zhang, Dong-Hua Yang
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Editorial Material
Cell Biology
Yancheng Tang, Liming Wang, Jiangjiang Qin, Yingying Lu, Han-Ming Shen, Hu-Biao Chen
Summary: Inhibition of PINK1-PRKN-mediated mitophagy enhances the anticancer efficacy of magnolol and could be a promising therapeutic strategy for overcoming cancer drug resistance and improving the therapeutic efficacy of anticancer agents.
Article
Biochemistry & Molecular Biology
Jinyun Dong, Jing Yang, Wenkai Yu, Haobin Li, Maohua Cai, Jing-Li Xu, Han-Dong Xu, Yun-Fu Shi, Xiaoqing Guan, Xiang-Dong Cheng, Jiang-Jiang Qin
Summary: The study found that the quinolin-6-yl substituted derivative KL-6 effectively inhibited the growth and invasion of gastric cancer cells, and induced apoptosis. The compound also showed anticancer activity in a mouse model of gastric cancer without significant toxicity. Therefore, KL-6 may be a promising candidate for further research and development of gastric cancer treatment drugs.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Chunxiao Zhu, Xiaoqing Guan, Xinuo Zhang, Xin Luan, Zhengbo Song, Xiangdong Cheng, Weidong Zhang, Jiang-Jiang Qin
Summary: KRAS is the most frequently mutated oncogene in various tumor types and has been considered undruggable due to the lack of classic drug binding sites. However, the development of KRAS inhibitors has made KRAS mutations druggable. Despite remarkable clinical responses, resistance to monotherapy of KRAS inhibitors has been observed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors.
Article
Pharmacology & Pharmacy
Jing Yang, Lingling Wang, Xiaoqing Guan, Jiang-Jiang Qin
Summary: STAT3 is a critical player in cell signal transmission, making it a promising target for anticancer drug development. Many natural products have been shown to inhibit the STAT3 signaling pathway, demonstrating significant anticancer activities, but there is currently no FDA-approved STAT3 inhibitor.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Microbiology
Dongli Lv, Jinmei Xia, Xiaoqing Guan, Qiliang Lai, Beibei Zhang, Jianhui Lin, Zongze Shao, Sulan Luo, Dongting Zhangsun, Jiang-Jiang Qin, Weiyi Wang
Summary: Two new bioactive compounds were isolated from a deep-sea-derived fungus and their structures were determined. Compounds 1, 5-7 exhibited significant inhibition against Staphylococcus aureus, while compound 8 showed potent reduction in cell viability of gastric cancer cells.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Handong Xu, Can Hu, Yi Wang, Yunfu Shi, Li Yuan, Jingli Xu, Yanqiang Zhang, Jiahui Chen, Qin Wei, Jiangjiang Qin, Zhiyuan Xu, Xiangdong Cheng
Summary: Gastric cancer (GC) is a deadly malignancy that requires new therapeutic targets for effective treatment. Glutathione peroxidase-2 (GPx2) was found to be overexpressed in clinical GC samples and negatively correlated with prognosis. Knockdown of GPx2 inhibited GC progression and metastasis by suppressing the KYNU-kyn-AhR signaling pathway, which was activated by reactive oxygen species (ROS) accumulation.