Review
Pharmacology & Pharmacy
Sinan Ma, Jianai Ji, Yuanyuan Tong, Yuxuan Zhu, Junwei Dou, Xian Zhang, Shicheng Xu, Tianbao Zhu, Xiaoli Xu, Qidong You, Zhengyu Jiang
Summary: The article introduces the development of proteolysis targeting chimeras (PROTACs) technology and the advantages of non-small molecule PROTACs (NSM-PROTACs), and summarizes the progress of NSM-PROTACs so far.
ACTA PHARMACEUTICA SINICA B
(2022)
Review
Chemistry, Medicinal
Dazhao Mi, Yuzhan Li, Haijun Gu, Yan Li, Yihua Chen
Summary: Proteolysis-targeting chimeras (PROTACs) have gained significant attention as an emerging modality in drug discovery. After over 20 years of development, accumulated studies have shown that PROTACs offer unique advantages over traditional therapy in terms of target scope, efficacy, and overcoming drug resistance. However, the limited availability of E3 ligases, essential components of PROTACs, poses a challenge for their design. This review provides a systematic summary of the current status of E3 ligases and corresponding ligands for PROTACs design, including their discovery history, design principles, application benefits, and potential limitations. The prospects and future directions in this field are also briefly discussed.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Ioannis Avgeris, Dimanthi Pliatsika, Sotiris S. Nikolaropoulos, Manolis A. Fousteris
Summary: This review presents an overview of marketed antiandrogens and various interesting AR-targeting compounds from a pharmacochemical perspective. The design approaches, structural evolution, and structure-activity relationships of prominent compound classes are emphasized. The transition from traditional steroidal AR antagonists to modern AR-targeting PROTACs is discussed, providing a comprehensive overview of AR-targeting molecules for PCa treatment.
BIOORGANIC CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Poornachandra Yedla, Ahmed O. Babalghith, Vindhya Vasini Andra, Riyaz Syed
Summary: Cancer treatments with targeted therapy, specifically Proteolysis-Targeting Chimeras (PROTACs), have gained significant attention for their unique mechanism of action and ability to target undruggable proteins. This review focuses on PROTACs in prostate cancer, highlighting their superiority over conventional inhibitors, and discussing the challenges and future prospects in this field. It also explores the underlying pathophysiology of prostate cancer and provides insights into the structural design and linker strategies for PROTAC molecules.
Article
Cell Biology
Mayao Luo, Yifan Zhang, Zhuofan Xu, Chenwei Wu, Yuedian Ye, Rui Liu, Shidong Lv, Qiang Wei
Summary: The combination therapy of tautomycin and enzalutamide could achieve a more comprehensive inhibition of androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC). Enzalutamide enhanced tautomycin-induced AR degradation by competing with residual androgens, while tautomycin decreased ARv7 levels through AR degradation. This combination therapy may represent a new therapeutic strategy for CRPC.
CELL DEATH DISCOVERY
(2022)
Article
Biochemistry & Molecular Biology
Tao Zhou, Tingting Chen, Bin Lai, Wenfeng Zhang, Xi Luo, Ding Xia, Weihua Fu, Jie Xu
Summary: The study reveals that FBXW2 functions as a tumor suppressor in prostate cancer by promoting EGFR ubiquitination and degradation, leading to repression of cell proliferation and metastasis.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Xiao-Li Zhou, Fang Zhao, Yong-Tao Xu, Yuan-Yuan Guan, Tong Yu, Yi-Zhe Zhang, Ying-Chao Duan, Yuan Zhao
Summary: Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) is an effective strategy for drug discovery, especially in cancer therapy. BET proteins, as therapeutic targets in cancer treatment, have been extensively studied and there have been recent advances in BET-targeting PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yin Sun, Ruifeng Wang, Yu Sun, Lin Wang, Yanli Xue, Jingkai Wang, Tianxiao Wu, Wenbo Yin, Qiaohua Qin, Yixiang Sun, Dongmei Zhao, Maosheng Cheng
Summary: The intracellular non-receptor tyrosine protein kinase Focal adhesion kinase (FAK) plays a crucial role in tumor survival, invasion, metastasis, and angiogenesis. The study demonstrates the importance of addressing both FAK kinase and scaffolding functions and introduces the use of PROTAC technology to simultaneously eliminate these functions. The novel FAK PROTAC B5 exhibits potent affinity and degradation activity against FAK, as well as powerful antiproliferative effects and inhibition of cell migration and invasion. The results suggest that PROTAC B5 holds promise as a lead compound for cancer drug discovery.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Rui Li, Miao Liu, Zhenya Yang, Jiao Li, Yuxin Gao, Ruirong Tan
Summary: PROteolysis TArgeting Chimeras (PROTACs) is an innovative technique that selectively degrades target proteins via the ubiquitin-proteasome system, offering advantages over traditional protein inhibitor drugs in terms of efficacy, selectivity, and overcoming drug resistance in cancer therapy. In this review, we comprehensively discuss the historical milestones, structures, mechanisms, and application of PROTACs in targeting tumor-related targets. We also provide a list of representative PROTACs based on CRBN, VHL, MDM2, or cIAP1 E3 ligases, as well as those undergoing clinical trials for anti-cancer activity.
Article
Biochemistry & Molecular Biology
Jian-Jia Liang, Hang Xie, Rui-Hua Yang, Ni Wang, Zi-Jun Zheng, Chen Zhou, Ya-Lei Wang, Zhi-Jia Wang, Hong-Min Liu, Li-Hong Shan, Yu Ke
Summary: In this study, novel PROTACs containing different linker phthalimide degrons were designed, synthesized, and evaluated for their AR degradation activity. Compound A16 showed the best AR binding affinity and degradation activity, while B10 exhibited effective internalization and visualization in LNCaP cells. Molecular docking of A16 with AR and the DDB1-CRBN E3 ubiquitin ligase complex provides guidance for designing new PROTAC degrons targeting AR in prostate cancer therapy. This research represents progress towards developing novel and improved AR PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Alessandro Giraudo, Marco Pallavicini, Cristiano Bolchi
Summary: The alpha 9- and alpha 7-containing nicotinic acetylcholine receptors play key roles in physiological and pathological processes. Selective ligands for these receptors are important research tools and potential therapeutic agents. While there is a wealth of information on alpha 7-nAChR ligands, the understanding of selective alpha 9-nAChR ligands is limited. This review provides a comprehensive overview of the latter, along with recent updates on alpha 7-nAChR ligands.
PHARMACOLOGICAL RESEARCH
(2023)
Review
Pharmacology & Pharmacy
Diksha Choudhary, Amritpal Kaur, Pargat Singh, Gaurav Chaudhary, Rajwinder Kaur, Mohammad F. Bayan, Balakumar Chandrasekaran, Saeed M. Marji, Reema Ayman
Summary: This review article summarizes the mechanism, uses, advantages, disadvantages, challenges, and future development aspects of PROTACs as a drug strategy.
PHARMACOLOGY & THERAPEUTICS
(2023)
Review
Biochemistry & Molecular Biology
Andrew R. Conery, Jennifer L. Rocnik, Patrick Trojer
Summary: The approval of the first histone methyltransferase inhibitor in 2020 marks a significant milestone in the field of targeted manipulation of chromatin regulatory pathways for cancer treatment. Despite the complexity of identifying key targets for therapeutic intervention, approaches in chemical biology have played a critical role in discovering key nodes in these pathways and translating them into potential cancer therapies. This review highlights the importance of chemical probes, drug candidates, and translational strategies in maximizing the impact of epigenetic writer enzymes in cancer therapy.
NATURE CHEMICAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Xuelian Liu, Anjin Wang, Yuying Shi, Mengyuan Dai, Miao Liu, Hong-Bing Cai
Summary: The epigenetic regulation of gene functions is closely associated with cancer development and progression. Reprogramming the cancer epigenome landscape is a promising target therapy for treating cancer and reversing drug resistance. Proteolytic targeted chimeras (PROTACs) are emerging therapeutic modality that selectively degrade proteins via the ubiquitin-proteasome system. Many PROTAC degraders have been designed in the field of epigenetic cancer therapy, and targeting epigenetic proteins with PROTACs can enhance target druggability and improve mechanistic understanding of cancer epigenetic regulation. This review focuses on the progress in developing PROTAC degraders and PROTAC drugs targeting epigenetics in cancer, and discusses challenges and future opportunities for this field.
Review
Biochemistry & Molecular Biology
Hua Gao, Jing-Yi Zhang, Li-Jie Zhao, Yuan-Yuan Guo
Summary: Rearrangements of the ALK gene in tumors lead to abnormal expression and activation, which can be inhibited by ALK tyrosine kinase inhibitors (TKIs) to elicit anti-tumor effects. Four generations of ALK-positive targeted drugs have been investigated, providing a promising outlook for patients.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dong Liang, Chen Yu, Xiaojun Qin, Xingye Yang, Xuhui Dong, Mingzhao Hu, Lupei Du, Minyong Li
Summary: In this study, three small-molecule fluorescent probes targeting c-Met were developed and their design strategies were explored. The probes exhibited fluorescence properties suitable for imaging and showed inhibitory activities against c-Met, particularly probe 16. Binding between the probes and c-Met was confirmed using fluorescence polarization assays and flow cytometry analysis. Cell imaging demonstrated that these probes could label c-Met on living cells. This research is of significance for the development of c-Met kinase inhibitors and tumor pathology research.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Organic
Xingye Yang, Xiaojun Qin, Huimin Ji, Lupei Du, Minyong Li
Summary: Bioluminescence imaging (BLI) is a widely used visual method for real-time detection of physiological and pathological processes. One of the most commonly used bioluminescent systems is the firefly luciferin system, which has been successfully applied in various fields such as analyzing physiological processes, monitoring the environment, diagnosing diseases, screening candidate drugs, and evaluating therapeutic effects.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Analytical
Wenhua Li, Zhao Ma, Jiwei Chen, Gaopan Dong, Lupei Du, Minyong Li
Summary: A series of new fluorescent ligands with high binding affinity and visualizing ability for beta-adrenergic receptors (beta-ARs) have been successfully developed. Compound L5 showed the most favorable combination of properties, including high affinity, remarkable fluorescence enhancement upon binding, and the ability to visualize beta-ARs in living cells without wash steps. Additionally, a NanoLuc-based binding assay using compound 1,5 has been developed for high-throughput screening of beta-ARs.
ANALYTICAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Xiang Li, Minyong Li
Summary: Developing effective drug screening methods is crucial for antitumor drug research. Patient-derived xenograft (PDX) tumor animal models and zebrafish as a screening model organism enable accurate and rapid discovery of lead compounds in the preclinical stage, while elucidating tumor pathogenesis.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Chemistry, Medicinal
Zhenzhen Li, Siyue Ma, Ling Zhang, Shuxin Zhang, Zhao Ma, Lupei Du, Minyong Li
Summary: Targeted protein degradation strategies have been developed to explore new therapeutic avenues and tools for biological investigation. In this study, we introduce a novel approach called heat shock protein 90-mediated targeting chimeras (HEMTACs) to induce protein degradation by connecting a target protein to HSP90. We demonstrate the successful application of HEMTACs for cyclin-dependent kinase 4 and 6 (CDK4/6), highlighting their potential as a valuable addition to TPD strategies, particularly proteolysis-targeting chimera technology.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Mutian Jia, Yuanyuan Wang, Jie Wang, Danhui Qin, Mengge Wang, Li Chai, Yue Fu, Chunyuan Zhao, Chengjiang Gao, Jihui Jia, Wei Zhao
Summary: This study demonstrates that STING-triggered autophagy plays a crucial role in eliminating pathogens and limiting STING-induced interferon responses. Specifically, myristic acid attenuates IFN responses while enhancing STING-dependent autophagy, contributing to immune homeostasis. Mechanistically, myristic acid promotes N-myristoylation of ARF1, which controls STING membrane trafficking and enhances autophagy degradation of the STING complex. Targeting myristic acid and N-myristoylation could be a promising approach for treating diseases caused by aberrant STING activation.
NATURE COMMUNICATIONS
(2023)
Editorial Material
Chemistry, Multidisciplinary
Zhao Ma, Minyong Li
ACS CENTRAL SCIENCE
(2023)
Review
Pharmacology & Pharmacy
Zhenzhen Li, Siyue Ma, Shuxin Zhang, Zhao Ma, Lupei Du, Minyong Li
Summary: Targeted protein degradation strategies, such as PROTACs, are effective for intracellular protein degradation, but new technologies are emerging for the degradation of extracellular and membrane proteins. These technologies are still in their early stages of application, despite some progress in the field. In this review, we summarize and review the therapeutic potential of existing technologies for extracellular and membrane protein degradation.
DRUG DISCOVERY TODAY
(2023)
Review
Immunology
Ying Qin, Wei Zhao
Summary: The NLRP3 inflammasome is a crucial complex involved in inflammation, and posttranslational modifications of NLRP3 play critical roles in controlling inflammation severity. Various modifications, including phosphorylation, ubiquitination, and SUMOylation, can affect the activity, stability, and localization of NLRP3, as well as its association with other inflammasome components. This review provides an overview of NLRP3 PTMs and their roles in controlling inflammation, as well as potential anti-inflammatory drugs targeting NLRP3 PTMs.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2023)
Article
Immunology
Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao
Summary: cGAS is a DNA sensor that activates innate immune responses. Polyamines spermine and spermidine inhibit cGAS activity by inducing a conformational change in DNA, decreasing its binding affinity with cGAS. SAT1, a polyamine metabolism enzyme, regulates cGAS activation by inhibiting cellular DNA accumulation.
Article
Immunology
Feng Liu, Wanxin Zhuang, Bin Song, Yuan Yang, Junqi Liu, Yi Zheng, Bingyu Liu, Jie Zheng, Wei Zhao, Chengjiang Gao
Summary: In this study, the researchers discovered that K63-linked polyubiquitin chains loaded on MAVS can be recognized by RIG-I to initiate MAVS aggregation. They also identified Ube2N as a major enzyme involved in the polyubiquitination of MAVS and found that it cooperates with Riplet and TRIM31 to promote unanchored polyubiquitination. Additionally, they identified USP10 as a deubiquitinating enzyme that removes unanchored polyubiquitin chains from MAVS.
CELLULAR & MOLECULAR IMMUNOLOGY
(2023)
Article
Chemistry, Analytical
Yuhao Chen, Tiantian Zhao, Zhuang Miao, Tianguang Huang, Meiyuan Chen, Yi Zhao, Ao Hai, Qingrong Qi, Ping Feng, Minyong Li, Bowen Ke
Summary: In this study, a selective bioluminescent probe (CBP 1) was designed, synthesized, and evaluated for the real-time detection of CES2. This probe offers a promising approach for understanding the physiological functions and underlying mechanisms of CES2.
Article
Immunology
Wanxin Zhuang, Lei Zhang, Yi Zheng, Bingyu Liu, Chunhong Ma, Wei Zhao, Suxia Liu, Feng Liu, Chengjiang Gao
Summary: Inflammasomes are crucial for the innate immune system, and dysregulation of their activation can have negative impacts on human health. This study reveals that USP3 acts as a key regulator of ASC ubiquitination, enhancing its stability and promoting inflammasome activation.
CELLULAR & MOLECULAR IMMUNOLOGY
(2022)