Article
Chemistry, Multidisciplinary
Xiaoyu Zhang, Lena M. Luukkonen, Christie L. Eissler, Vincent M. Crowley, Yu Yamashita, Michael A. Schafroth, Shota Kikuchi, David S. Weinstein, Kent T. Symons, Brian E. Nordin, Joe L. Rodriguez, Thomas G. Wucherpfennig, Ludwig G. Bauer, Melissa M. Dix, Dean Stamos, Todd M. Kinsella, Gabriel M. Simon, Kristen A. Baltgalvis, Benjamin F. Cravatt
Summary: Ligand-induced protein degradation through electrophilic PROTACs has been shown to degrade proteins in human cells by engaging specific cysteines in the poorly characterized E3 ligase substrate adaptor DCAF11. These findings suggest DCAF11 as a potential E3 ligase for ligand-induced protein degradation via electrophilic PROTACs, providing new insights for the development of targeted protein degradation compounds.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
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)
Article
Biochemistry & Molecular Biology
Kusal T. G. Samarasinghe, Saul Jaime-Figueroa, Michael Burgess, Dhanusha A. Nalawansha, Katherine Dai, Zhenyi Hu, Adrian Bebenek, Scott A. Holley, Craig M. Crews
Summary: The study introduces TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription factor degradation, demonstrating successful degradation of oncogenic DNA-binding proteins NF-kB and brachyury. The findings suggest TRAFTAC technology could be a promising approach for inducing degradation of other transcription factors both in vitro and in vivo.
CELL CHEMICAL BIOLOGY
(2021)
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
Po-Han Chen, Zhenyi Hu, Elvira An, Ifunanya Okeke, Sijin Zheng, Xuanmeng Luo, Angela Gong, Saul Jaime-Figueroa, Craig M. Crews
Summary: PhosTACs is a novel therapeutic approach that recruits phosphatases to dephosphorylate specific proteins, thereby modulating protein activity. This method can offer target gain-of-function opportunities and may represent a new direction in drug development.
ACS CHEMICAL BIOLOGY
(2021)
Review
Chemistry, Medicinal
Qiong Li, Li Zhou, Siyuan Qin, Zhao Huang, Bowen Li, Ruolan Liu, Mei Yang, Edouard C. Nice, Huili Zhu, Canhua Huang
Summary: The success of inhibitor-based therapeutics is limited by therapeutic resistance driven by the undruggable proteome. Proteolysis targeting chimera (PRO-TAC) technology, which degrades proteins involved in specific biological processes, offers a new way to overcome this constraint. By connecting an E3 ubiquitin ligase ligand with a protein of interest (POI)-binding ligand, PRO-TAC molecules can selectively degrade undruggable proteins via the ubiquitin-proteasome system (UPS).
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Xinyi Li, Wenchen Pu, Qingquan Zheng, Min Ai, Song Chen, Yong Peng
Summary: PROTAC is an engineered technique for targeted protein degradation, which recruits target protein and E3 ubiquitin ligase to trigger the degradation of target protein. It has great potential in cancer therapy and offers advantages over traditional anti-cancer therapies.
Article
Chemistry, Multidisciplinary
Zhenyi Hu, Po-Han Chen, Wenxue Li, Todd Douglas, John Hines, Yansheng Liu, Craig M. Crews
Summary: Microtubule-associated protein tau is crucial for microtubule assembly and stabilization. Tau hyperphosphorylation is implicated in the development of Alzheimer's disease and tauopathies. In this study, we used small molecule-based PhosTACs to induce efficient and sustained tau dephosphorylation by recruiting tau to PP2A, a native tau phosphatase. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. Our findings suggest that PhosTACs represent a potential avenue for disease-modifying therapies for tauopathies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Yanyan Miao, Qianqian Gao, Menghan Mao, Chao Zhang, Liqun Yang, Yang Yang, Da Han
Summary: This study describes a platform for the targeted degradation of membrane-associated proteins using bispecific aptamer chimeras, which efficiently shuttle therapeutically relevant membrane proteins to lysosomes for degradation. This method provides a universal platform for biochemical research and potential therapeutics using readily synthesized aptamer materials.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Oncology
Yangping Wu, Jingliao Zhang, Xiaofan Zhu, Yingchi Zhang
Summary: PROTACs, as a novel drug development approach, degrade target proteins via the ubiquitin-proteasome system, showing clinical potential in the treatment of hematologic malignancies. Despite their numerous advantages, PROTACs face challenges in design, synthesis, evaluation, and clinical application.
Article
Chemistry, Medicinal
Charu Chaudhry
Summary: Proteolysis targeting chimeras (PROTACs) are novel protein degraders that utilize the ubiquitin-proteasome system (UPS) to degrade disease-causing proteins. A mathematical model was developed to study the use of irreversible covalent chemistry in targeted protein degradation (TPD), considering thermodynamic and kinetic factors. The model highlights the advantages of covalency in enhancing ternary complex formation and degradation. Covalent E3 PROTACs show enhanced catalytic efficiency and have the potential to improve the degradation of fast turnover targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Tao Wang, Liang Sun, Tianyu Ren, Min Hou, Ying Long, Jian-Hui Jiang, Jianjun He
Summary: Protein-degrading chimeras, such as lysosome-targeting exosomes (LYTEXs), are effective drug modalities for treating diseases caused by abnormal protein expression. LYTEXs, genetically engineered exosomes expressing multivalent single-chain fragment variables, can selectively degrade membrane protein targets, providing a generalizable and easy-to-prepare platform for modulating surface protein expression.
Article
Multidisciplinary Sciences
Satoshi Yamanaka, Hirotake Furihata, Yuta Yanagihara, Akihito Taya, Takato Nagasaka, Mai Usui, Koya Nagaoka, Yuki Shoya, Kohei Nishino, Shuhei Yoshida, Hidetaka Kosako, Masaru Tanokura, Takuya Miyakawa, Yuuki Imai, Norio Shibata, Tatsuya Sawasaki
Summary: Lenalidomide is an effective drug for treating hematological cancers, but has teratogenic effects on fetuses. This study identifies modifications that enhance the selectivity and effectiveness of lenalidomide as a standalone molecular glue or integrated in PROTACs.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Tuan M. Nguyen, Vedagopuram Sreekanth, Arghya Deb, Praveen Kokkonda, Praveen K. Tiwari, Katherine A. Donovan, Veronika Shoba, Santosh K. Chaudhary, Jaron A. M. Mercer, Sophia Lai, Ananthan Sadagopan, Max Jan, Eric S. Fischer, David R. Liu, Benjamin L. Ebert, Amit Choudhary
Summary: Proteolysis-targeting chimeras (PROTACs) are capable of inducing the degradation of target proteins by bringing them close to E3 ligases. However, the widely used E3 ligase recruiter, pomalidomide, can also cause the degradation of other proteins, resulting in off-target effects. This study developed a high-throughput platform to investigate off-target degradation and identified several zinc-finger (ZF) proteins as off-targets of pomalidomide-based PROTACs. By modifying the pomalidomide analogues at the appropriate position, off-target degradation of ZF proteins was reduced. Applying this design principle, anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation were developed.
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)
Editorial Material
Biotechnology & Applied Microbiology
Stacey-Lynn Paiva
NATURE REVIEWS DRUG DISCOVERY
(2019)
Editorial Material
Biotechnology & Applied Microbiology
Stacey-Lynn Paiva
NATURE REVIEWS DRUG DISCOVERY
(2020)
Editorial Material
Biotechnology & Applied Microbiology
Stacey-Lynn Paiva
NATURE REVIEWS DRUG DISCOVERY
(2020)
Editorial Material
Biotechnology & Applied Microbiology
Stacey-Lynn Paiva
NATURE REVIEWS DRUG DISCOVERY
(2020)
Retraction
Chemistry, Multidisciplinary
Dhanusha A. Nalawansha, Stacey-Lynn Paiva, Diane N. Rafizadeh, Mariell Pettersson, Liena Qin, Craig M. Crews
ACS CENTRAL SCIENCE
(2020)
Editorial Material
Biotechnology & Applied Microbiology
Stacey-Lynn Paiva
NATURE REVIEWS DRUG DISCOVERY
(2020)
Article
Biochemistry & Molecular Biology
Deepto Mozumdar, Amy Doerner, Justin Y. Zhang, Diane N. Rafizadeh, Alanna Schepartz
Editorial Material
Chemistry, Multidisciplinary
Stacey-Lynn Paiva
NATURE REVIEWS CHEMISTRY
(2021)
Review
Microbiology
Halie M. Rando, Nils Wellhausen, Soumita Ghosh, Alexandra J. Lee, Anna Ada Dattoli, Fengling Hu, James Brian Byrd, Diane N. Rafizadeh, Ronan Lordan, Yanjun Qi, Yuchen Sun, Christian Brueffer, Jeffrey M. Field, Marouen Ben Guebila, Nafisa M. Jadavji, Ashwin N. Skelly, Bharath Ramsundar, Jinhui Wang, Rishi Raj Goel, Yoson Park, Simina M. Boca, Anthony Gitter, Casey S. Greene
Summary: The novel coronavirus SARS-CoV-2 poses a significant global threat after emerging in China in late 2019. Previous research on SARS and MERS has been valuable in identifying approaches to treating and preventing COVID-19. The medical and scientific communities have rapidly responded to the COVID-19 crisis and identified numerous candidate therapeutics.
Editorial Material
Chemistry, Multidisciplinary
Stacey-Lynn Paiva
Summary: Ammonium bicarbonate can enhance the reactivity of amines with carbon dioxide in microdroplet reactions.
NATURE REVIEWS CHEMISTRY
(2022)
Editorial Material
Chemistry, Multidisciplinary
Stacey-Lynn Paiva
NATURE REVIEWS CHEMISTRY
(2021)
Editorial Material
Chemistry, Multidisciplinary
Stacey-Lynn Paiva
NATURE REVIEWS CHEMISTRY
(2021)
Editorial Material
Chemistry, Multidisciplinary
Stacey-Lynn Paiva
NATURE REVIEWS CHEMISTRY
(2022)