Article
Biochemistry & Molecular Biology
Salma Darwish, Ehab Ghazy, Tino Heimburg, Daniel Herp, Patrik Zeyen, Rabia Salem-Altintas, Johannes Ridinger, Dina Robaa, Karin Schmidtkunz, Frank Erdmann, Matthias Schmidt, Christophe Romier, Manfred Jung, Ina Oehme, Wolfgang Sippl
Summary: This study developed proteolysis targeting chimeras (PROTACs) of HDAC8 based on potent and selective HDAC8 inhibitors. The selective HDAC8 PROTACs showed anti-neuroblastoma activity in cells, indicating their potential as targeted therapy for neuroblastoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Se Yong Park, Raju Gurung, Jung Ho Hwang, Alam Zeb, Jong-Ik Hwang, Sung Jean Park, Han-Joo Maeng, Dongyun Shin, Seung Hyun Oh
Summary: Oxidative stress caused by excessive accumulation of reactive oxygen species (ROS) is a major factor in the development of human diseases. Activation of NRF2 by inhibiting KEAP1 has shown promising results in combating oxidative stress-related diseases. In this study, a proteolysis-targeting chimera (PROTAC) called SD2267 was developed, which induced the degradation of KEAP1 and subsequent activation of NRF2.
Article
Biochemistry & Molecular Biology
Tianzhi Wen, Jian Chen, Wenqian Zhang, Jiyan Pang
Summary: In this study, a series of small-molecule degraders were designed and synthesized based on a known alpha-synuclein aggregation inhibitor sery384. Compound 5 exhibited significant degradation effect on alpha-synuclein aggregates in a time- and dose-dependent manner in vitro.
Article
Chemistry, Medicinal
Eva Reznickova, Sona Krajcovicova, Miroslav Perina, Marketa Kovalova, Miroslav Soural, Vladimir Krystof
Summary: A novel pomalidomide-based PROTAC has been designed and prepared for the degradation of FLT3-ITD and CDK9 proteins in AML patients. The results of biochemical and cellular experiments showed selectivity and proteasome-dependent mechanism of action, resulting in the blockage of FLT3-ITD downstream signaling pathways, activation of apoptosis, cell cycle arrest, and reduced expression of crucial genes involved in AML pathogenesis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Cell Biology
Ludovica Lospinoso Severini, Francesca Bufalieri, Paola Infante, Lucia Di Marcotullio
Summary: This paragraph discusses the importance of post-translational modifications, such as ubiquitylation, and introduces the PROteolysis-TArgeting Chimera (PROTAC) technology. PROTACs utilize the cell's Ubiquitin-Proteasome System to degrade target proteins and have potential therapeutic applications in cancer treatment.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Qi Zhang, Peizheng Yan, Pan Zhao, Dongsheng Zhao, Heran Cao, Jing Lu, Beibei Mao
Summary: This study utilized MLN0128 as a ligand to target mTOR, and designed several potential small molecule PROTACs using diverse intermediate linkage chains with pomalidomide. The PROTAC compounds showed mTOR inhibitory activity and suppressed MCF-7 cell proliferation.
CHEMICAL & PHARMACEUTICAL BULLETIN
(2023)
Review
Chemistry, Medicinal
Deping Li, Dongmin Yu, Yan Li, Renze Yang
Summary: Proteolysis targeting chimera (PROTAC) technology, a promising targeted protein degradation approach, has gained significant attention in recent years. This bibliometric analysis provides insights into the frontiers and hotspots of PROTAC, including publication trends, geographical distribution, influential authors and journals, as well as keywords and common targets in this field. The analysis highlights the importance of understanding the current and developing areas of study in PROTAC research.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Yujeong Moon, Seong Ik Jeon, Man Kyu Shim, Kwangmeyung Kim
Summary: Proteolysis-targeting chimeras (PROTACs) are potential therapeutic strategy for cancer therapy, capable of inducing degradation of oncogenic proteins. They recruit E3 ligases and utilize the ubiquitin-proteasome pathway for specific catalysis. However, poor water solubility and low cell permeability limit their pharmacokinetic properties, hence requiring suitable delivery systems for cancer immunotherapy.
Article
Chemistry, Medicinal
Dingqiang Fu, Yi Yuan, Fengming Qin, Yan Xu, Xin Cui, Guangxun Li, Shaohua Yao, Yun Deng, Zhuo Tang
Summary: This study designed and synthesized a series of degraders using PROTAC technology that directly targeted human tyrosinase, with the best PROTAC TD9 showing promising results in inducing tyrosinase degradation and highlighting the potential for treating tyrosinase-related disorders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Markella Konstantinidou, Asmaa Oun, Pragya Pathak, Bidong Zhang, Zefeng Wang, Frans ter Brake, Amalia M. Dolga, Arjan Kortholt, Alexander Domling
Summary: The paper introduces rational design and synthetic methodologies for proteolysis-targeting chimeras (PROTACs) targeting the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two potent brain-penetrating kinase inhibitors were selected and modified to assemble a cereblon-targeting PROTAC, showing strong kinase inhibition and cell penetration capability. However, data on target protein degradation remains inconclusive, and reasons for inefficient degradation are discussed further.
Article
Chemistry, Multidisciplinary
Jaeki Min, Anand Mayasundari, Fatemeh Keramatnia, Barbara Jonchere, Seung Wook Yang, Jamie Jarusiewicz, Marisa Actis, Sourav Das, Brandon Young, Jake Slavish, Lei Yang, Yong Li, Xiang Fu, Shalandus H. Garrett, Mi-Kyung Yun, Zhenmei Li, Stanley Nithianantham, Sergio Chai, Taosheng Chen, Anang Shelat, Richard E. Lee, Gisele Nishiguchi, Stephen W. White, Martine F. Roussel, Patrick Ryan Potts, Marcus Fischer, Zoran Rankovic
Summary: IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, affecting their efficacy; Novel CRBN binders, phenyl glutarimide (PG) analogues, were designed with high affinity and improved stability; Discovery of PG PROTAC 4c as a potent degrader of BET proteins, supporting the utility of PG derivatives in CRBN-directed PROTACs design.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Oncology
Gabriel LaPlante, Wei Zhang
Summary: The ubiquitin-proteasome system plays a critical role in regulating protein levels and activity within cells, and its dysregulation is associated with various human diseases, including cancer. Targeting this system for inhibition in cancer therapy has shown promise, with proteasome inhibitors already being successfully used in multiple myeloma treatment. Furthermore, recent advancements in the development of targeted protein degradation strategies utilizing the UPS machinery, such as PROTACs, offer new avenues for cancer therapeutics.
Article
Chemistry, Medicinal
Mikhail Krasavin, Maria Adamchik, Andrey Bubyrev, Christopher Heim, Samuel Maiwald, Daniil Zhukovsky, Petr Zhmurov, Alexander Bunev, Marcus D. Hartmann
Summary: In order to enhance the chemical toolkit for targeted protein degradation, the authors developed a new series of non-thalidomide Cereblon (CRBN) ligands. By using a thio-Michael addition reaction, readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides. These compounds were evaluated for their affinity to human CRBN and their binding modes were studied through X-ray crystallography. The newly identified Cereblon ligands show promising potential for the synthesis of novel PROTAC protein degraders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Wu Du
Summary: This review discusses the development of AR-targeting PROTACs over the last two decades, including medicinal chemistry strategies, pharmacokinetic profiles, and clinical development. Using AR targeting PROTACs as a case study, this review provides an overview of how PROTAC technology has advanced from a revolutionary concept to drug candidates that benefit patients.
FUTURE MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Ryan Kolb, Umasankar De, Sajid Khan, Yuewan Luo, Myung-Chul Kim, Haijun Yu, Chaoyan Wu, Jiao Mo, Xin Zhang, Peiyi Zhang, Xuan Zhang, Nicholas Borcherding, Daniel Koppel, Yang-Xin Fu, Song Guo Zheng, Dorina Avram, Guangrong Zheng, Daohong Zhou, Weizhou Zhang
Summary: The pharmacological degradation of BCL-X-L preferentially induces apoptosis of tumor-infiltrating Tregs, promoting CD8 T cell activation and effective suppression of tumor growth without causing damage to normal tissues or thrombocytopenia. This finding suggests that targeting BCL-X-L could be a potential therapeutic strategy for cancer immunotherapy.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Shuang Mei, Su Jiang, Yuting Wang, Han Jing, Peng Yang, Miao-Miao Niu, Jindong Li, Kai Yuan, Yan Zhang
Summary: This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Hyeonjun Lee, Ju Yeon Lee, Hyunsoo Jang, Hye Young Cho, Minhee Kang, Sang Hyun Bae, Suin Kim, Eunji Kim, Jaebong Jang, Jin Young Kim, Young Ho Jeon
Summary: By using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, we identified new chemical moieties that bind to the target sites of the protein of interest, allowing for reversible binding and protein degradation. This method has the potential to expand the application of PROTAC technology.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Bingsi Wang, Mingxu Ma, Yusen Dai, Pengfei Yu, Liang Ye, Wenyan Wang, Chunjie Sha, Huijie Yang, Yingjie Yang, Yunjing Zhu, Lin Dong, Shujuan Wei, Linlin Wang, Jingwei Tian, Hongbo Wang
Summary: Breast cancer is a common malignant tumor in women, and drug resistance remains a clinical challenge. In this study, a novel compound, G-5b, was developed with potent antagonistic and degradation activities comparable to the current drug fulvestrant. G-5b also showed improved stability and solubility. Mechanistically, G-5b engages the proteasome pathway to degrade ER, inhibiting the ER signaling pathway and inducing apoptosis and cell cycle arrest. In animal models, G-5b exhibited superior pharmacokinetics and pharmacodynamics properties. Overall, G-5b is a promising long-acting SERD worthy of further investigation and optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Michal Sulik, Diana Fontinha, Dietmar Steverding, Szymon Sobczak, Michal Antoszczak, Miguel Prudencio, Adam Huczynski
Summary: This study describes the synthesis of the first-in-class ivermectin derivatives obtained through derivatization of the C13 position, along with the unexpected rearrangement of the macrolide ring. These derivatives show potential for antiparasitic activity and are important for the development of new antiparasitic agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Jun Liu, Qiu-Xian Chen, Wen-Fu Wu, Dong Wang, Si -Yu Zhao, Jia-Hao Li, Yi-Qun Chang, Shao-Gao Zeng, Jia-Yi Hu, Yu-Jie Li, Jia-Xin Du, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai -Bo Zhou, Yong-Heng Wang, Jian Zou, Ping-Hua Sun
Summary: A new anti-infective drug strategy has been discovered to attenuate virulence and modulate inflammation caused by drug-resistant Pseudomonas aeruginosa infections. Compound 5f inhibits biofilm formation, macrophage migration, and inflammatory response induced by P. aeruginosa, showing potential as a novel candidate against drug-resistant infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Liuzeng Chen, Ke Wang, Lingyun Wang, Wei Wang, Lifan Wang, Jia Li, Xiaohan Liu, Mengya Wang, Banfeng Ruan
Summary: In this study, a series of novel anti-inflammatory compounds were designed and synthesized based on the natural product pterostilbene skeleton. Among them, compound 8 showed the highest activity and exhibited its effects through inhibition of pro-inflammatory cytokines by blocking the NF-KB/MAPK signaling pathway. Compound 8 also demonstrated a good relieving effect on acute colitis in mice and showed good safety in acute toxicity experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Si-Min Liang, Gui-Bin Liang, Hui-Ling Wang, Hong Jiang, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
Summary: A series of novel multi-target antitumor agents were designed, synthesized, and evaluated. Some compounds exhibited significant antitumor activity and one compound showed excellent efficacy, limited toxicity, and low resistance. Further mechanism studies revealed that the compound exerted antitumor effects through multiple pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)