Article
Cell Biology
Martin P. Schwalm, Lena M. Berger, Maximilian N. Meuter, James D. Vasta, Cesear R. Corona, Sandra Roehm, Benedict-Tilman Berger, Frederic Farges, Sebastian M. Beinert, Franziska Preuss, Viktoria Morasch, Vladimir V. Rogov, Sebastian Mathea, Krishna Saxena, Matthew B. Robers, Susanne Mueller, Stefan Knapp
Summary: E3 ligases play a crucial role in regulating protein homeostasis by recruiting substrate proteins to the proteasomal degradation machinery. Recent research has focused on the Baculovirus IAP Repeat (BIR) family of E3 ligases, which contain a structurally conserved but diverse protein interaction domain. The Inhibitors of Apoptosis (IAP) family, which typically have three BIR domains, are promising drug targets. However, there is currently a lack of assay tools to evaluate the selectivity of inhibitors in this target area.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Chemistry, Medicinal
Harbinder Singh, Devendra K. Agrawal
Summary: Protease-targeted chimeras (PROTACs) are a novel therapeutic approach that utilizes the ubiquitin-proteasome system for targeted protein degradation. PROTACs based on small-molecule inhibitors have several advantages and cereblon-based PROTACs have promising clinical potential.
FUTURE MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Samuel Maiwald, Christopher Heim, Birte Hernandez Alvarez, Marcus D. Hartmann
Summary: Repurposing E3 ubiquitin ligases for targeted protein degradation via customized molecular glues or PROTACs is important, but limited by our incomplete understanding of E3 ligases and their ligand space. A quantitative assay based on the thermophoretic behavior of a custom reporter ligand offers a potential high-throughput screening method for discovering and characterizing E3 ligase ligands.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Pharmacology & Pharmacy
Marcin Cieslak, Marta Slowianek
Summary: The traditional low-molecular-weight drugs target specific biological targets with receptor or enzymatic activity to inhibit their function. However, there are disease proteins that cannot be targeted using this approach. PROTACs, on the other hand, can bind both the protein of interest and the E3 ubiquitin ligase complex, leading to degradation. This review focuses on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis.
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)
Review
Biochemistry & Molecular Biology
Jaeseok Lee, Youngjun Lee, Young Mee Jung, Ju Hyun Park, Hyuk Sang Yoo, Jongmin Park
Summary: Target protein degradation is an emerging strategy for therapeutics discovery. Proteolysis-targeting chimera (PROTAC) utilizes cellular ubiquitin-dependent proteolysis system to efficiently degrade a protein of interest. However, the current PROTAC technology is limited by the cell type specific expression of E3 ligases and resistance to CRBN or VHL ligands. Therefore, the discovery of new E3 ligase ligands is crucial for improving PROTAC technology.
Article
Chemistry, Medicinal
Guoqiang Dong, Yu Ding, Shipeng He, Chunquan Sheng
Summary: Targeted protein degradation through molecular glues is a promising area in drug discovery, offering unique biological activities and physicochemical properties. While classical molecular glue degraders have been serendipitously identified, rational discovery and design strategies are now rapidly emerging.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Can Zhao, Henian Wang, Wenhu Zhan, Xiaoqing Lv, Xiaodong Ma
Summary: The use of proximity-mediated effects to disrupt pathogenic proteins of interest (POIs) has become a powerful alternative to traditional drug design methods. Recent advancements include the degradation of various types of POIs, stabilization of target proteins, recruitment of immunophilins, and post-translational modifications. These advances provide new avenues for innovative drug discovery to combat human malignancies and other major diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Multidisciplinary
Liena Qin, Han Dai, Junfeng Wang
Summary: Targeted protein degraders offer an event-driven pharmacological approach to drug proteins that were traditionally considered undruggable. This review discusses several key considerations in the discovery and development of targeted protein degradation drugs.
FRONTIERS IN CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Bayonle Aminu, Julia Fux, Evan Mallette, Nathaniel Petersen, Wei Zhang
Summary: The Ubiquitin Variant Induced Proximity (UbVIP) technology allows for targeted degradation of proteins, showing potential as a therapeutic approach for human diseases. By utilizing synthetic UbV binders and designing multi-domain fusion proteins, researchers were able to induce proteasomal degradation of a nucleus-localized protein 53BP1. This study demonstrates the suitability of UbV technology for developing protein-based molecules for targeted degradation and identifying novel E3 ligases.
Review
Pharmacology & Pharmacy
Si-Min Qi, Jinyun Dong, Zhi-Yuan Xu, Xiang-Dong Cheng, Wei-Dong Zhang, Jiang-Jiang Qin
Summary: PROTAC technology is an effective method for degrading target proteins through the ubiquitin-proteasome system, with promising applications in cancer treatment. The first oral PROTACs have shown encouraging results in clinical trials, sparking greater enthusiasm for PROTAC research.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Marine C. Aublette, Tom A. Harrison, Elizabeth J. Thorpe, Morgan S. Gadd
Summary: The Ser/Thr protein kinase Wee1 plays a regulatory role in DNA damage by phosphorylating CDK1. The selective inhibitor AZD1775 has off target effects on other protein kinases. This study describes the synthesis and evaluation of Wee1-degrading PROTACs with different linkers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Zhiqiang Sun, Bulian Deng, Zichao Yang, Ruiyao Mai, Junli Huang, Zeli Ma, Ting Chen, Jianjun Chen
Summary: This study designed and synthesized a series of HDAC8 degraders based on the PROTAC strategy. Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 and achieved maximal degradation effect at a specific time point after treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Joshua D. Hansen, Matthew Correa, Matt Alexander, Mark Nagy, Dehua Huang, John Sapienza, Gang Lu, Laurie A. LeBrun, Brian E. Cathers, Weihong Zhang, Yang Tang, Massimo Ammirante, Rama K. Narla, Joseph R. Piccotti, Michael Pourdehnad, Antonia Lopez-Girona
Summary: Acute myeloid leukemia poses a significant clinical challenge with poor survival and high relapse rates. CC-90009, a novel protein degrader targeting GSPT1 for proteasomal degradation, represents a promising therapeutic approach currently in phase 1 clinical development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Na Yang, Bo Kong, Zhaohong Zhu, Fei Huang, Liliang Zhang, Tao Lu, Yadong Chen, Yanmin Zhang, Yulei Jiang
Summary: Targeted protein degradation (TPD) technology, such as PROTACs, has become widespread in the past 20 years and greatly accelerates the development of disease treatment. Unlike small inhibitors, targeted protein degraders can target undruggable targets and overcome drug resistance through ubiquitin-proteasome pathway (UPP) and lysosome pathway. This review discusses different degradation technologies and provides a basis for future research.
MOLECULAR DIVERSITY
(2023)
Review
Pharmacology & Pharmacy
Karlie R. Sharma, Christine M. Colvis, Griffih P. Rodgers, Douglas M. Sheeley
Summary: There are many genes within the druggable genome that have not been studied, and the US National Institutes of Health's program provides resources to explore these genes, with the potential for rapid impact on human health.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Mohammad Sameer Khan, B. H. Jaswanth Gowda, Waleed H. Almalki, Tanuja Singh, Amirhossein Sahebkar, Prashant Kesharwani
Summary: Mitochondria-specific functional liposomes hold great potential for cancer therapy. This review discusses the association between mitochondria and tumor formation, as well as the advantages of liposomes in delivering drugs to mitochondria.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Choong Yong Ung, Cristina Correia, Hu Li, Christopher M. Adams, Jennifer J. Westendorf, Shizhen Zhu
Summary: With increasing human life expectancy, the global medical burden of chronic diseases is growing. Chronic diseases often involve malfunctioning of multiple organs, and understanding the interorgan crosstalk is crucial to understanding the etiology of chronic diseases. Researchers have proposed the locked-state model (LoSM) and cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. The findings have important clinical implications for improving treatments for chronic diseases.
DRUG DISCOVERY TODAY
(2024)