Article
Oncology
Tarryn Willmer, Victoria Damerell, Shannon Smyly, Danica Sims, Michelle Du Toit, Stephanie Ncube, Musalula Sinkala, Dhirendra Govender, Edward Sturrock, Jonathan M. Blackburn, Sharon Prince
Summary: The study identifies TBX3 as upregulated in various sarcoma subtypes and requiring nucleolin as a cofactor to promote sarcomagenesis. Disruption of the TBX3-nucleolin interaction by AS1411 shows selective anti-cancer activity in sarcoma cells, providing a novel approach for treating sarcomas.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Yan Xu, Yi Yuan, Ding-Qiang Fu, Yi Fu, Shan Zhou, Wan-Ting Yang, Xu-Yang Wang, Guang-Xun Li, Juan Dong, Feng Du, Xin Huang, Qi-Wei Wang, Zhuo Tang
Summary: This study achieves targeted degradation of RNA-binding proteins (RBPs) using the aptamer-based RNA-PROTAC technique. RBPs, traditionally considered undruggable targets, can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, and a small molecule recruits E3 ubiquitin ligase to induce proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets have been successfully degraded by replacing the RCBE module on the RNA scaffold, and simultaneous degradation of multiple target proteins has been achieved by inserting more functional RNA oligonucleotides into the RNA scaffold.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Wenqing Li, Jiabin Zhang, Li Guo, Qiantao Wang
Summary: This study explores the use of molecular dynamics simulation and molecular mechanics combined with the generalized Born and surface area continuum solvation (MM/GBSA) method to solve the three-body problem in PROTAC modeling. The results validate the accuracy of the approach and demonstrate the qualitative and quantitative importance of PROTAC-induced protein-protein interactions in its modeling.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Chunlan Pu, Yuanyuan Liu, Rui Deng, Qingjia Xu, Shirui Wang, Hongjia Zhang, Dan Luo, Xinyu Ma, Yu Tong, Rui Li
Summary: The treatment of breast cancer has advanced significantly, but triple negative breast cancer (TNBC) remains difficult to treat. Cyclin-dependent kinases (CDK) 4/6 have been identified as effective targets for breast cancer treatment. In this study, a series of CDK4/6 degraders based on DCAF16 were designed and synthesized, and compound A4 showed potent inhibitory activity against CDK4/6. Additionally, A4 demonstrated lower toxicity in normal cells compared to Palbociclib and exhibited therapeutic potential in TNBC xenograft models.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Dehao Yu, Heli Fan, Zhili Zhou, Ying Zhang, Jing Sun, Luo Wang, Yuanyuan Jia, Junyu Tian, Anahit Campbell, Wenyi Mi, Huabing Sun
Summary: H2O2-inducible PROTAC precursors 2/5 are activated by endogenous H2O2 in cancer cells to release active PROTACs 1/4 for effective degradation of targeted proteins. This method exhibits high H2O2-induced BRD4 degradation activity and cytotoxicity in cancer cells, enhancing selectivity of PROTACs.
Article
Chemistry, Medicinal
Haixia Liu, Xinyu Ding, Linyi Liu, Qianglong Mi, Quanju Zhao, Yubao Shao, Chaowei Ren, Jinju Chen, Ying Kong, Xing Qiu, Nicola Elvassore, Xiaobao Yang, Qianqian Yin, Biao Jiang
Summary: Protein degradation through CRBN-recruiting PROTACs has shown promising potential in targeting oncogenic fusion protein BCR-ABL, providing a potential therapeutic strategy for chronic myeloid leukemia.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Haruna Tsujimura, Miyako Naganuma, Nobumichi Ohoka, Takao Inoue, Mikihiko Naito, Genichiro Tsuji, Yosuke Demizu
Summary: Targeted protein degradation (TPD) using chimeric molecules like proteolysis-targeting chimeras (PROTACs) has been studied as a strategy to selectively degrade intracellular proteins by utilizing the ubiquitin-proteasome system (UPS). Nucleic acid aptamers have shown potential as ligands for targeting proteins for degradation. In this study, nucleic acid aptamers were linked to estrogen receptor alpha (ER alpha) and E3 ubiquitin ligase ligands to construct chimeric molecules that could degrade ER alpha via UPS. These findings demonstrate the development of novel aptamer-based PROTACs for targeting intracellular proteins.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Oncology
Monica Cubillos-Rojas, Guillem Loren, Yusuf Z. Hakim, Xavier Verdaguer, Antoni Riera, Angel R. Nebreda
Summary: PROTACs are compounds composed of two fragments that bring together a specific protein and a ubiquitinating enzyme, leading to ubiquitination and degradation of the targeted protein. This paper describes a type of PROTAC that effectively reduces the expression of the p38 alpha protein in cancer cells and tumors in mice. These compounds offer a promising strategy for targeting p38 alpha in potential therapeutic applications.
Article
Chemistry, Medicinal
Shulei Zhu, Jieyu Liu, Donghuai Xiao, Peipei Wang, Jingkun Ma, Xiaobei Hu, Jingfeng Fu, Yubo Zhou, Jia Li, Wei Lu
Summary: This study reports a novel Wee1 degrader based on PROTAC technology, which effectively degrades cellular Wee1 protein and has potential applications in cancer therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Le Guo, Jin Liu, Xueqing Nie, Taobo Wang, Zhi-xiong Ma, Dan Yin, Weiping Tang
Summary: Proteolysis Targeting Chimera (PROTAC) has emerged as a novel therapeutic strategy. The development of PROTACs faces the challenge of screening multiple parameters. In this study, a two-stage method was proposed to rapidly synthesize and screen PROTACs simultaneously. Using this method, the researchers successfully developed a PROTAC for FGFR and identified a potent degrader.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Le Guo, Yaxian Zhou, Xueqing Nie, Zhongrui Zhang, Zhen Zhang, Chunrong Li, Taobo Wang, Weiping Tang
Summary: PROTAC is a commonly used technology for targeted protein degradation, and the Rapid-TAC platform enables rapid synthesis of PROTAC through traceless coupling reaction, saving time and facilitating screening of active protein degraders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Nanoscience & Nanotechnology
Xiao Liang, Yudi Wang, Hui Shi, Mengmeng Dong, Haobo Han, Quanshun Li
Summary: This study successfully created AS1411 aptamer-functionalized micelles for the co-delivery of doxorubicin and miR-519c, demonstrating promising anti-cancer efficacy in the HepG2 cell model. The micelles exhibited favorable tumor penetration and cellular uptake abilities, improving intracellular drug accumulation and efficiently inhibiting tumor growth through active targeting and MDR reversal.
INTERNATIONAL JOURNAL OF NANOMEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Huiru Xie, Wei Xu, Jing Liang, Yang Liu, Chenxi Zhuo, Xiaoxue Zou, Weihong Luo, Jianping Xiao, Yu Lin, Lixia Chen, Hua Li
Summary: EZH2, a member of PcG, is oncogenic and its overexpression can lead to cancer. Tazemetostat (EPZ6438), an EZH2 inhibitor, can block the methylation catalytic activity of EZH2. However, solely inhibiting EZH2 is not effective in blocking tumor development. In this study, proteolytic targeting chimera technology was employed to enhance the antiproliferative potency of EPZ6438 by degrading oncogenic EZH2 activity. Several PROTACs were synthesized by combining EPZ6438 with different E3 ligase ligands, and compound E-3P-MDM2 exhibited the highest activity. It degraded EZH2, EED, and SUZ12 proteins in a concentration and dose-dependent manner, inhibited the expression of H3K27me3, and showed much stronger antiproliferative activity than EPZ6438.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lihua Bie, Yue Wang, Fuze Jiang, Zhen Xiao, Lianjun Zhang, Jing Wang
Summary: This study proposes a feasible binding mode for the recognition of cell surface nucleolin by AS1411 aptamer and provides atomic-level descriptions for its high affinity and specific binding. The molecular basis of this specific binding is elucidated, which can guide the rational design of AS1411-based aptamers.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Haili Wang, Chuchu Li, Xiaoqing Liu, Mingliang Ma
Summary: PI3K kinase plays a crucial role in cellular processes, and its overexpression is associated with various cancers. PROTAC technology, using the ubiquitin-proteasome system, can degrade target proteins. This study successfully connected a highly active PI3K inhibitor to VHL ligand and developed PROTAC molecules targeting PI3K kinase.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Tao Zhong, Xiaofan Wu, Wei Xie, Xiangrui Luo, Ting Song, Shuang Sun, Youguang Luo, Dengwen Li, Min Liu, Songbo Xie, Jun Zhou
Summary: ENKD1 is identified as a critical regulator of epidermal stratification by modulating the cell-division orientation of basal keratinocytes and promoting astral microtubule stability. Depletion of ENKD1 leads to thinner epidermis and defective spindle orientation, which can be rescued by introducing the microtubule-binding domain of ENKD1.
CELL DEATH AND DIFFERENTIATION
(2022)
Review
Biochemistry & Molecular Biology
Yuyang Li, Min Liu, Songbo Xie
Summary: Phage display is a powerful high-throughput screening technology widely used in bioengineering and biomedicine for affinity determination towards a target by presenting functional peptides, proteins, or antibody fragments on phage capsid surfaces. With the advancement of next-generation sequencing and microfluidics, phage display has become an even more powerful and popular tool for drug discovery and development.
CURRENT MEDICINAL CHEMISTRY
(2021)
Letter
Cell Biology
Huixian Ma, Feifei Qi, Li Ji, Songbo Xie, Jie Ran, Min Liu, Jinmin Gao, Jun Zhou, Xuebiao Yao
JOURNAL OF MOLECULAR CELL BIOLOGY
(2022)
Article
Oncology
Bo Zhang, Hui Peng, Mi Zhou, Lei Bao, Chenliang Wang, Feng Cai, Hongxia Zhang, Jennifer E. Wang, Yanling Niu, Yan Chen, Yijie Wang, Kimmo J. Hatanpaa, John A. Copland, Ralph J. DeBerardinis, Yingfei Wang, Weibo Luo
Summary: This study reveals that BCAT1 plays a role in promoting the growth of IDHWT GBM. Loss of BCAT1 protein leads to the killing of IDHWT GBM cells by x-ketoglutarate (AKG), which can be reversed by reexpression of BCAT1 or supplementation with its downstream metabolic products, branched-chain ketoacids (BCKA). This finding uncovers a targetable metabolic vulnerability in the most common subset of GBM and provides a therapeutic strategy to improve glioblastoma treatment.
Article
Cell Biology
Tangming Guan, Xiao Yang, Hui Liang, Jiayi Chen, Yan Chen, Yingjie Zhu, Tongzheng Liu
Summary: This study reveals the important regulatory mechanism of breast cancer metastasis and chemoresistance, namely the USP9X-Snail1 axis, and provides a rationale for potential therapeutic interventions in the treatment of TNBC.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Chemistry, Analytical
Songbo Xie, Jingrui Li, Shuang Sun, Wei Chen, Haisu Cheng, Yinlong Song, Yuyang Li, Min Liu, Xueliang Zhu, Xin Liang, Jun Zhou
Summary: This study developed a peptide probe called TUBright that can label in vitro reconstituted microtubules with high signal-to-noise ratio. TUBright does not interfere with the dynamic behaviors of microtubules and microtubule-associated proteins.
ANALYTICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Maowu Luo, Lei Bao, Yan Chen, Yuanyuan Xue, Yong Wang, Bo Zhang, Chenliang Wang, Chase D. Corley, Jeffrey G. McDonald, Ashwani Kumar, Chao Xing, Yisheng Fang, Erik R. Nelson, Jennifer E. Wang, Yingfei Wang, Weibo Luo
Summary: The histone reader ZMYND8 is selectively expressed in breast cancer stem cells (BCSCs) and promotes breast tumor initiation through its epigenetic functions by regulating 27-HC metabolism, leading to the accumulation of 27-HC in BCSCs and activation of liver X receptor.
Review
Pharmacology & Pharmacy
Yijie Wang, Xiong Liu, Weixiao Huang, Junjie Liang, Yan Chen
Summary: Alterations in protein ubiquitination and HIF signaling contribute to tumorigenesis and tumor progression. ROS upregulation in tumors has multiple effects on HIF signaling and the ubiquitin system. Multiple E3 ligases and UBDs work together to regulate the expression and activity of HIF, helping cancer cells cope with hypoxia. Understanding the complex networks between E3 ligase, UBDs, ROS, and HIF provides insights into the cellular response to hypoxia and identifies novel molecular targets for cancer treatment.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Cell Biology
Bo Zhang, Yan Chen, Lei Bao, Weibo Luo
Summary: This study demonstrates that hypoxia upregulates the expression of GPT2 in GBM cells through HIF-2 activation. GPT2 is localized in the nucleus and mitochondria and can decrease α-ketoglutarate levels in GBM cells. Inhibition of GPT2 can reduce GBM cell growth and migration, and knockout of GPT2 inhibits GBM tumor growth in mice.
Article
Cell Biology
Wei Xie, Siqi Gao, Yunfan Yang, Hongjie Li, Junyan Zhou, Mingzhen Chen, Song Yang, Yijun Zhang, Liang Zhang, Xiaoqian Meng, Songbo Xie, Min Liu, Dengwen Li, Yan Chen, Jun Zhou
Summary: This study reveals that the deubiquitinating enzyme CYLD plays a critical role in cardiac gap junction assembly. CYLD interacts with plakoglobin and removes lysine 63-linked polyubiquitin chains from plakoglobin, enhancing its interaction with the desmoplakin/end-binding protein 1 complex and promoting microtubule-dependent transport of connexin 43 (Cx43) to the cell membrane.
Letter
Oncology
Lingping Kong, Fanlu Meng, Sijin Wu, Ping Zhou, Ruixin Ge, Min Liu, Linlin Zhang, Jun Zhou, Diansheng Zhong, Songbo Xie
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Jia Yang, Yang Liu, Hanxiao Yin, Songbo Xie, Linlin Zhang, Xifeng Dong, Hua Ni, Weiwen Bu, Hongbo Ma, Peng Liu, Haiyan Zhu, Rongxia Guo, Lei Sun, Yue Wu, Juan Qin, Baofa Sun, Dengwen Li, Hongbo R. Luo, Min Liu, Chenghao Xuan, Jun Zhou
Summary: The study reveals an important role for histone deacetylase 6 (HDAC6) and isocitrate dehydrogenase 1 (IDH1) in regulating the homeostasis of hematopoietic stem and progenitor cells (HSPCs). HDAC6 interacts with and deacetylates IDH1, inhibiting its catalytic activity and promoting HSPC proliferation by changing gene expression patterns.
Article
Chemistry, Analytical
Songbo Xie, Jingrui Li, Shuang Sun, Wei Chen, Haisu Cheng, Yinlong Song, Yuyang Li, Min Liu, Xueliang Zhu, Xin Liang, Jun Zhou
Summary: This study develops a peptide probe called TUBright that can label in vitro reconstituted microtubules. It provides flexible labeling of microtubules without interfering with their dynamic behaviors.
ANALYTICAL CHEMISTRY
(2022)