Article
Chemistry, Multidisciplinary
Yuan Liu, Xu Qian, Chunyan Ran, Longjie Li, Ting Fu, Dan Su, Sitao Xie, Weihong Tan
Summary: The selective removal of misfolded, aggregated, or aberrantly overexpressed proteins is crucial in protein-dominated biological processes. Targeted protein degradation (TPD) technology, utilizing small molecules or antibodies as protein recognition tools, has great potential in various fields. Aptamers, which are short RNA or DNA oligonucleotides, are actively used in designing and constructing TPD technology. This article provides an overview of TPD technology, its application challenges, and recent advances in aptamer-based TPD technology.
Article
Pharmacology & Pharmacy
Qian-Qian Zhou, Hai -Tao Xiao, Fan Yang, Yong-Dan Wang, Ping Li, Zu-Guo Zheng
Summary: The development and application of traditional drugs, especially inhibitors, has become the mainstream drug development. Targeted protein degradation (TPD) technology, based on the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), has emerged as a promising method to remove specific disease-related proteins. Different TPD strategies, such as PROTAC, MG, LYTAC, CMA-targeting chimeras, AUTAC, ATTEC, and AUTOTAC, can change undruggable protein targets in human cells to druggable, expanding the therapeutic prospect of refractory diseases.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Nathaniel J. Henning, Lydia Boike, Jessica N. Spradlin, Carl C. Ward, Gang Liu, Erika Zhang, Bridget P. Belcher, Scott M. Brittain, Matthew J. Hesse, Dustin Dovala, Lynn M. McGregor, Rachel Valdez Misiolek, Lindsey W. Plasschaert, David J. Rowlands, Feng Wang, Andreas O. Frank, Daniel Fuller, Abigail R. Estes, Katelyn L. Randal, Anoohya Panidapu, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, Daniel K. Nomura
Summary: Many diseases caused by aberrant protein ubiquitination and degradation could benefit from targeted protein stabilization (TPS). In this study, deubiquitinase-targeting chimeras (DUBTACs) were used to stabilize specific proteins degraded in a ubiquitin-dependent manner, leading to therapeutic benefits. Covalent chemoproteomic approaches were used to identify a ligand, EN523, that targeted a specific deubiquitinase. DUBTACs consisting of EN523 and a protein-targeting ligand were shown to stabilize the levels of disease-related proteins, showing promise for TPS.
NATURE CHEMICAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Nuwayo Ishimwe Sincere, Krishnan Anand, Sumel Ashique, Jing Yang, Chongge You
Summary: Targeted protein breakdown using PROTACs technology is a potential therapeutic strategy for conditions caused by abnormal protein production. PROTACs utilize an event-driven pharmacology to inhibit protein function and trigger its degradation. The development of potent, tissue- and cell-specific PROTAC compounds remains a challenge.
Article
Oncology
Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, David J. Weber, Vincent C. O. Njar
Summary: In this study, the researchers demonstrate the potential role of VNPP433-3 beta as a molecular glue that brings Androgen Receptor and MDM2 E3 ligase physically close in prostate cancer cells. This interaction promotes the degradation of AR through ubiquitination and inhibits the growth of prostate cancer cells.
Article
Chemistry, Multidisciplinary
Minghua Yuan, Yanan Chu, Yongtao Duan
Summary: PROTACs, composed of target protein binding moiety, a linker, and an E3 ubiquitin ligase binder, have shown promise in drug design. Research indicates that reversible covalent PROTACs may offer increased potency, selectivity, and duration of action, paving the way for future developments in challenging target degradations.
FRONTIERS IN CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Yue Zhong, Fanglian Chi, Hanyu Wu, Yunxiao Liu, Zhancheng Xie, Wenlong Huang, Wei Shi, Hai Qian
Summary: Targeted protein degradation technology represents a new therapeutic modality in drug discovery. Researchers are exploring optimized protein degraders to overcome the limitations of classical PROTACs and achieve more precise protein degradation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Andrew J. Tao, Gillian E. Gadbois, Stanley A. Buczynski, Fleur M. Ferguson
Summary: Targeted protein degraders are small molecules that can rapidly reduce the expression of target proteins. Recent studies have shown that degraders with specificity can be developed for subpopulations of target proteins.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2022)
Article
Cell Biology
Jinhuan Wu, Yuping Chen, Rui Li, Yaping Guan, Mu Chen, Hui Yin, Xiaoning Yang, Mingpeng Jin, Bingsong Huang, Xin Ding, Jie Yang, Zhe Wang, Yiming He, Qianwen Wang, Jian Luo, Ping Wang, Zhiyong Mao, Michael S. Y. Huen, Zhenkun Lou, Jian Yuan, Fanghua Gong
Summary: The study reveals that CDK2 regulates the ERK pathway through USP37, promoting cancer cell proliferation. Additionally, the combination of CDK1/2 and EGFR inhibitors shows a synergistic anticancer effect by reducing the stability and activity of ERK1/2.
JOURNAL OF CELL BIOLOGY
(2023)
Review
Chemistry, Medicinal
M. Elizabeth Sobhia, Harish Kumar, Sonia Kumari
Summary: The increasing significance of Targeted Protein Degradation (TPD) and PROTACs has attracted attention from the scientific community. PROTACs, acting as bifunctional robots, demonstrate strong binding affinity to the protein of interest (POI) and E3 ligase, facilitating the ubiquitination of POI. These molecules, driven by event-driven pharmacology, have broad applications in oncology, antiviral therapy, neurodegenerative diseases, acne, etc., providing researchers with immense possibilities. This review primarily compiles recent literature on PROTACs targeting various proteins, focusing on the design and development strategies, including molecular information of protein residues and linker design. The study also includes the rationalization of ternary complex formation using Artificial Intelligence, including machine and deep learning models, as well as traditional computational tools. Furthermore, the optimization of PROTACs chemistry and pharmacokinetic properties is discussed, along with advanced PROTAC designs for targeting complex proteins.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Siyu Chen, Jingliang Cui, Haiyan Chen, Bo Yu, Sihui Long
Summary: Targeted protein degradation is a key strategy in current cancer therapy, and Proteolysis targeting chimera (PROTAC) is a popular branch that induces target protein degradation by activating the ubiquitin-proteasome system. In addition to intracellular proteins, membrane proteins have also been reported to be degraded, and other effective membrane protein degradation strategies have emerged.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Anna Pasieka, Eleonora Diamanti, Elisa Uliassi, Maria Laura Bolognesi
Summary: Click chemistry and targeted protein degradation, two flourishing trends in medicinal chemistry. Can they be a winning combination? In this review, we provide the reader with selected examples offered by the combination of these two approaches trying to find a response to this question.
Review
Biochemistry & Molecular Biology
Jake A. Ward, Carles Perez-Lopez, Cristina Mayor-Ruiz
Summary: Degraders can induce the ubiquitination and degradation of disease-relevant proteins by targeting E3 ubiquitin ligases. This pharmacology offers a promising alternative to current therapeutic interventions and has the potential to broaden the range of targetable proteins. Biophysical and structural biology approaches are key in understanding degrader-induced ternary complex formation, and computational models are now being used to design new degraders. Effective crosstalk between experimental and computational strategies is crucial for advancements in the targeted protein degradation field.
Review
Chemistry, Medicinal
Hong-Yi Zhao, Minhang Xin, San-Qi Zhang
Summary: In recent years, targeted protein degradation (TPD), particularly proteolysis targeting chimeras, has experienced rapid development, displaying numerous advantages over small molecule inhibitors. A vast number of degraders against over 70 disease-related targets have been discovered, with degraders against estrogen receptor and androgen receptor advancing to phase II clinical trials. TPD technologies significantly broaden the scope of druggable targets and provide effective tools for addressing complex issues that cannot be resolved by traditional small molecule inhibitors. This review primarily focuses on the structures and biological activities of small molecule degraders, as well as the elucidation of mechanisms in emerging TPD technologies, while also highlighting the current challenges in the TPD field.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Pharmacology & Pharmacy
William Farnaby, Manfred Koegl, Darryl B. McConnell, Alessio Ciulli
Summary: Small-molecule targeted protein degraders known as PROTACs have shown potential to broaden drug target scope, address drug resistance, enhance target selectivity, and provide tissue specificity in cancer therapy. However, further development and refinement are needed to fully realize the benefits of this approach.
CURRENT OPINION IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Kristin M. Riching, Sarah Mahan, Cesear R. Corona, Mark McDougall, James D. Vasta, Matthew B. Robers, Marjeta Urh, Danette L. Daniels
ACS CHEMICAL BIOLOGY
(2018)
Article
Chemistry, Medicinal
Vittoria Zoppi, Scott J. Hughes, Chiara Maniaci, Andrea Testa, Teresa Gmaschitz, Corinna Wieshofer, Manfred Koegl, Kristin M. Riching, Danette L. Daniels, Andrea Spallarossa, Alessio Ciulli
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Alessio Ciulli, Suzanne O'Connor, Chun-Wa Chung, Ingo V. Hartung, Andrea Testa, Danette L. Daniels, Laura H. Heitman
Summary: This report provides an overview of the 17th EFMC Short Course on Medicinal Chemistry, highlighting the inclusion of the exciting topic of Targeted Protein Degradation. It summarizes the successful event and key lectures, as well as the diverse representation of attendees from Europe, the US, and South Africa.
Editorial Material
Pharmacology & Pharmacy
Asad M. Taherbhoy, Danette L. Daniels
Summary: This article introduces targeted protein degradation (TPD) and proposes multiple strategies using UBR5 as an E3 ligase to drive degradation of key transcriptional targets implicated in disease.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Review
Chemistry, Multidisciplinary
Kristin M. Riching, Elizabeth A. Caine, Marjeta Urh, Danette L. Daniels
Summary: Targeted protein degradation is a crucial therapeutic approach that requires optimization of multiple parameters to achieve rapid degradation, high potency, and sustained target loss. Degradation is only the first milestone in degrader development, and understanding the dynamic cellular degradation profiles is essential for discovering effective therapeutic agents more efficiently.
CHEMICAL SOCIETY REVIEWS
(2022)