Article
Chemistry, Medicinal
Francesca Ferlenghi, Laura Scalvini, Federica Vacondio, Riccardo Castelli, Nicole Bozza, Giuseppe Marseglia, Silvia Rivara, Alessio Lodola, Silvia La Monica, Roberta Minari, Pier Giorgio Petronini, Roberta Alfieri, Marcello Tiseo, Marco Mor
Summary: A new compound 11 was developed as a potent and irreversible inhibitor of EGFR(L858R/T790M/C797S), showing higher activity than osimertinib. However, it did not inhibit the triple mutant EGFR(del19/T790M/C797S).
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Yunfei Cheng, Gencheng Li, Christopher J. Smedley, Marie -Claire Giel, Seiya Kitamura, Jordan L. Woehl, Giulia Bianco, Stefano Forli, Joshua A. Homer, John R. Cappiello, Dennis W. Wolan, John E. Moses, K. Barry Sharpless
Summary: Diversity Oriented Clicking (DOC) is a method for rapidly synthesizing functional libraries by combining classical and modern click chemistries. It involves modulating the assembly of compounds through chemical diversification of core SuFExable hubs, such as 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs). The stereoselective Michael-type addition reactions from SASF hubs, including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides, provide high yielding beta-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification. These compounds show potential as covalent inhibitors of human neutrophil elastase, demonstrating the biological function aspect of click chemistry.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Laszlo Petri, Peter Aabranyi-Balogh, Noemi Csorba, Aaron Keeley, Jozsef Simon, Ivan Randelovic, Jozsef Tovari, Gitta Schlosser, Daniel Szabo, Laszlo Drahos, Gyoergy M. Keseru
Summary: SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Sulfonyl fluorides can label multiple nucleophilic amino acid residues, making them popular in both chemical biology and medicinal chemistry applications. In this study, a small sulfonyl fluoride library was synthesized and characterized, resulting in the identification of a 3-carboxybenzenesulfonyl fluoride warhead for tagging nucleophilic residues. Coupling diverse fragments to this warhead could yield a library of sulfonyl fluoride bits (SuFBits) for screening against protein targets, facilitated by mass spectrometry identification of weak fragments.
Article
Engineering, Environmental
Mian Bao, Hongru Feng, Yuanyuan Zheng, Haiwei Luo, Cuirong Sun, Yuanjiang Pan
Summary: PFOSF and PFHxSF were classified as persistent organic pollutants by the Stockholm Convention in 2009 and 2022, respectively. A novel chemical derivatization method was developed to quantitatively analyze trace amounts of PFOSF and PFHxSF in soil, by converting them to the corresponding perfluoroalkane sulfinic acids. This method demonstrated good linearity and sensitivity, with detection limits of 0.066 ng/g for PFOSF and 0.072 ng/g for PFHxSF in soil samples. By applying this method, high concentrations of PFOSF and PFHxSF were detected in an abandoned fluorochemical manufacturing facility even after 2 years of factory relocation.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Review
Pharmacology & Pharmacy
Huang Huang, Lyn H. Jones
Summary: This review highlights the limitations of cysteine labeling in covalent drug discovery and proposes the use of SuFEx chemistry to target a broader range of amino acids. Recent advances in SuFEx medicinal chemistry and chemical biology are described, including the development of covalent chemical probes that selectively engage various amino acid residues. The authors believe that covalent drug candidates utilizing sulfonyl exchange warheads to target residues beyond cysteine have the potential to enter clinical trials in the near future.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Chemistry, Organic
Dong-yu Zhu, Xue-jing Zhang, Ming Yan
Summary: Enantioselective conjugate addition of azlactones to ethylene sulfonyl fluoride has been achieved effectively via cooperative catalysis, providing structurally diverse azlactone sulfonyl fluoride derivatives for drug discovery purposes.
Article
Chemistry, Analytical
Xiaohan Chen, Youwen Zhang, Pearl Arora, Xiyun Guan
Summary: Different species can be detected using nanopores engineered with various recognition sites based on non-covalent interactions. This strategy allows for differentiation between species, making it potentially useful for molecular detection in medical and environmental applications.
ANALYTICAL CHEMISTRY
(2021)
Article
Chemistry, Analytical
Rebecca L. McCloud, Kun Yuan, Keira E. Mahoney, Dina L. Bai, Jeffrey Shabanowitz, Mark M. Ross, Donald F. Hunt, Ku-Lung Hsu
Summary: Chemical proteomics is a widely used method for investigating protein activity and small molecule ligand binding. LC-MS/MS is employed to assess covalent probe binding and inhibition, providing molecular information on targeted proteins and probe-modified sites. Key bioanalytical conditions have been revealed to guide future direct target site identification of complex irreversible probes and inhibitors.
ANALYTICAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Xuyan Song, Yunlu He, Bo Wang, Sanwen Peng, Xi Pan, Min Wei, Qiang Liu, Hua-Li Qin, Haolin Tang
Summary: A highly efficient method for synthesizing aryl sulfonyl fluorides from aryl sulfonyl chlorides using SO2F2 as a fluoride source has been developed, yielding up to 98% isolated yield under mild conditions. Gram scale experiments demonstrated the practicality of this new protocol.
Article
Chemistry, Organic
Grant A. L. Bare
Summary: There are various synthetic routes available to prepare sulfonyl fluorides (R-SO2F) that have been discovered for almost a century. However, these syntheses often have limitations in terms of scope, hazardous materials, and complex procedures. This study investigates a simple and mild procedure based on direct chloride/fluoride exchange from a sulfonyl chloride (R-SO2Cl) starting material in a KF and water/acetone biphasic mixture. Seventeen examples with high yield (84-100%) and wide scope are described.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Grant A. L. Bare
Summary: Numerous synthetic routes have been discovered for the preparation of sulfonyl fluorides (R-SO2F) over the past century. However, these syntheses are often limited by scope, hazardous materials, and complex procedures. This study investigates a simple and mild procedure based on direct chloride/fluoride exchange from a sulfonyl chloride (R-SO2Cl) starting material in a KF and water/acetone biphasic mixture. Seventeen examples with a wide scope are described, yielding high products (84-100%).
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Review
Food Science & Technology
Sevim Dalabasmaz, Omer Said Toker, Ibrahim Palabiyik, Nevzat Konar
Summary: This study explored the covalent and non-covalent reactions between cocoa polyphenols and proteins, and their potential effects on bioaccessibility, taking into account environmental and processing conditions. Understanding these interactions is essential for understanding the biological effects of polyphenols, developing nutritional strategies, and improving food processing and storage.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
(2023)
Article
Chemistry, Organic
Jie Chen, Dong-yu Zhu, Xue-jing Zhang, Ming Yan
Summary: An enantioselective Michael addition has been developed for the synthesis of structurally diverse isatin-derived alpha-(trifluoromethyl)imine derivatives with excellent yields and enantioselectivities, which are valuable candidates for drug discovery.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Sophia Bellia, Lara I. Teodoro, Antonio J. Barbosa, Matthias Zeller, Arsalan Mirjafari, Patrick C. Hillesheim
Summary: The study examines the differences in the interactions between fluoride and chloride in a sulfonyl ester functional group. It is found that fluoride does not participate in hydrogen interactions, while chloride does. However, fluoride atom forms close interactions with several π bonds. Additionally, the sulfonyl oxygens have comparable interactions for both moieties.
Article
Chemistry, Organic
Min Liu, Wenjian Tang, Hua-Li Qin
Summary: A new sulfonyl fluoride reagent (E)-2-methoxye-thene-1-sulfonyl fluoride (MeO-ESF) was developed and successfully applied for the construction of enaminyl sulfonyl fluoride (N-ESF). This protocol provides a highly atom-economical access to diverse N-ESF and produces CH3OH as the sole byproduct under mild and environmentally benign conditions.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Mingxing Teng, Marlise R. Luskin, Sandra W. Cowan-Jacob, Qiang Ding, Doriano Fabbro, Nathanael S. Gray
Summary: This review discusses the recent progress in the treatment of chronic myeloid leukemia (CML) and highlights the discovery and mechanism of action of allosteric inhibitors. The therapeutic potential of these inhibitors in delaying the development of acquired resistance is also explored. The article emphasizes the importance of understanding the fundamental regulatory mechanisms of kinases and presents key lessons learned from this program.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Ram K. Modukuri, Zhifeng Yu, Zhi Tan, Hai Minh Ta, Melek Nihan Ucisik, Zhuang Jin, Justin L. Anglin, Kiran L. Sharma, Pranavanand Nyshadham, Feng Li, Kevin Riehle, John C. Faver, Kevin Duong, Sureshbabu Nagarajan, Nicholas Simmons, Stephen S. Palmer, Mingxing Teng, Damian W. Young, Joanna S. Yi, Choel Kim, Martin M. Matzuk
Summary: The study identified compounds with BET BD1 specificity, including CDD-787 and CDD-956, which exhibited high affinity and selectivity and demonstrated potent anti-leukemic activity in acute myeloid leukemia.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Andrology
Qiuji Ye, Hassane Belabed, Yong Wang, Zhifeng Yu, Murugesan Palaniappan, Jian-Yuan Li, Stacey A. Kalovidouris, Kevin R. MacKenzie, Mingxing Teng, Damian W. Young, Yoshitaka Fujihara, Martin M. Matzuk
Summary: By developing a biophysical assay and using DNA-encoded chemical library (DECL) screening and off-DNA hit validation strategy, this study discovered a PDCL2 ligand for male contraception. The binding affinity between the PDCL2 ligand and PDCL2 was confirmed and determined by an affinity selection mass spectrometry assay combined with liquid chromatography tandem mass spectrometry (ASMS/LC-MS/MS).
Article
Chemistry, Medicinal
Wenzhi Ji, Eric S. Wang, Theresa D. Manz, Jie Jiang, Katherine A. Donovan, Xianmixinuer Abulaiti, Eric S. Fischer, Lewis C. Cantley, Tinghu Zhang, Nathanael S. Gray
Summary: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), consisting of three members (alpha, beta, and gamma) in mammals, have attracted attention as potential therapeutic targets due to their involvement in regulating various vital cellular signaling pathways. Among them, PI5P4K gamma shows distinct expression patterns and has been implicated in cancer and neurodegenerative diseases. A novel PI5P4K gamma degrader, JWZ-1-80, has been developed and characterized, exhibiting potent degradation activity and selective targeting towards PI5P4K gamma via the ubiquitin-proteasome system, which makes it a valuable tool compound for further investigations on the biological functions of PI5P4K gamma.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Alexander Hanzl, Eleonora Barone, Sophie Bauer, Hong Yue, Radoslaw P. Nowak, Elisa Hahn, Eugenia V. Pankevich, Anna Koren, Stefan Kubicek, Eric S. Fischer, Georg E. Winter
Summary: Targeted protein degradation (TPD) is a new pharmacology approach that induces proximity between a protein of interest (POI) and an E3 ubiquitin ligase using small-molecule degraders. However, only a small percentage of E3s can be co-opted with degraders due to a lack of discovery approaches. This study focuses on NEDD8 conjugation and develops a scalable assay to identify compounds that alter the interactome of a specific E3 ligase.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Multidisciplinary Sciences
Jiazhi Li, Longfei Wang, Quentin Hahn, Radoslaw P. Nowak, Thibault Viennet, Esteban A. Orellana, Shourya S. Roy Burman, Hong Yue, Moritz Hunkeler, Pietro Fontana, Hao Wu, Haribabu Arthanari, Eric S. Fischer, Richard I. Gregory
Summary: Chemical modifications of RNA play a crucial role in various biological processes. N-7-methylguanosine (m(7)G) is essential for the integrity and stability of a large group of tRNAs. The METTL1-WDR4 complex acts as a methyltransferase that modifies G46 in specific tRNAs, and its dysregulation is implicated in tumorigenesis. However, the mechanism of tRNA substrate recognition and regulation of METTL1-WDR4 remains unknown.
Article
Genetics & Heredity
Wubing Zhang, Shourya S. Roy Burman, Jiaye Chen, Katherine A. Donovan, Yang Cao, Chelsea Shu, Boning Zhang, Zexian Zeng, Shengqing Gu, Yi Zhang, Dian Li, Eric S. Fischer, Collin Tokheim, X. Shirley Liu
Summary: Targeted protein degradation has become a promising therapeutic approach to eliminate previously undruggable proteins. This study developed a machine learning model, MAPD, to accurately predict the degradability of protein targets. The model showed potential for drug development targeting disease-causing proteins.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2022)
Article
Chemistry, Multidisciplinary
Mingxing Teng, Jie Jiang, Eric S. Wang, Qixiang Geng, Sean T. Toenjes, Katherine A. Donovan, Nada Mageed, Hong Yue, Radoslaw P. Nowak, Jinhua Wang, Eric D. Fischer, Theresa S. Manz, Lewis C. Cantley, Nathanael S. Gray
Summary: This study identifies a highly potent PIP4K2C binder TMX-4102 and develops a bivalent degrader TMX-4153 that selectively degrades endogenous PIP4K2C. These findings provide important insights into the biological roles and therapeutic potential of PIP4K2C.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Multidisciplinary Sciences
Moritz Hunkeler, Cyrus Y. Jin, Eric S. Fischer
Summary: Tightly regulating apoptosis is crucial for the development of multicellular organisms and preventing diseases like cancer and neurodegeneration. Caspase activation is key to apoptosis, and inhibitor of apoptosis proteins (IAPs) are important for restraining caspase activity and can be targeted therapeutically. IAPs, in turn, are regulated by proapoptotic factors derived from mitochondria like SMAC and HTRA2. By studying the structures of human baculoviral IAP repeat-containing protein 6 (BIRC6) bound to SMAC, caspases, and HTRA2 through cryo-electron microscopy, we gain a molecular understanding of how BIRC6 inhibits caspase activity and how it is released by SMAC.
Review
Chemistry, Medicinal
Qi Miao, Vilas D. Kadam, Ayan Mukherjee, Zhi Tan, Mingxing Teng
Summary: Chemically induced proximity-based targeted protein degradation has become a prominent paradigm in drug discovery, and additional E3 ubiquitin ligases are being harnessed to enrich the arsenal of this therapeutic approach to tackle drug resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemical Research Methods
Hong Yue, Radoslaw P. Nowak, Daan Overwijn, N. Connor Payne, Stephanie Fischinger, Caroline Atyeo, Evan C. Lam, Kerri St. Denis, Lauren K. Brais, Yoshinobu Konishi, Romanos Sklavenitis-Pistofidis, Lindsey R. Baden, Eric J. Nilles, Elizabeth W. Karlson, Xu G. Yu, Jonathan Z. Li, Ann E. Woolley, Irene M. Ghobrial, Jeffrey A. Meyerhardt, Alejandro B. Balazs, Gali Alter, Ralph Mazitschek, Eric S. Fischer
Summary: Serological assays play an important role in diagnosing and monitoring infectious diseases. However, current methods have limitations in terms of technology and sample types. In this study, we developed a new serological assay based on TR-FRET technology, which showed exceptional versatility, scalability, and sensitivity. It outperformed or matched existing strategies in terms of sensitivity, specificity, and precision. This assay was successfully applied to measure antibody levels against different viruses and can be extended to other antigens.
CELL REPORTS METHODS
(2023)
Article
Biochemistry & Molecular Biology
Radoslaw P. Nowak, Leah Ragosta, Fidel Huerta, Hu Liu, Scott B. Ficarro, Justin T. Cruite, Rebecca J. Metivier, Katherine A. Donovan, Jarrod A. Marto, Eric S. Fischer, Breanna L. Zerfas, Lyn H. Jones
Summary: This study developed efficient PROTAC degraders using covalent CRBN ligands, which showed enhanced pharmacodynamics and expanded the scope of targets for heterobifunctional degraders.
RSC CHEMICAL BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Rob S. Sellar, Adam S. Sperling, Mikolaj Slabicki, Jessica A. Gasser, Marie E. McConkey, Katherine A. Donovan, Nada Mageed, Dylan N. Adams, Charles Zou, Peter G. Miller, Ravi K. Dutta, Steffen Boettcher, Amy E. Lin, Brittany Sandoval, Vanessa A. Quevedo Barrios, Veronica Kovalcik, Jonas Koeppel, Elizabeth K. Henderson, Emma C. Fink, Lu Yang, Anthony Chan, Sheela Pangeni Pokharel, Erik J. Bergstrom, Rajan Burt, Namrata D. Udeshi, Steven A. Carr, Eric S. Fischer, Chun-Wei Chen, Benjamin L. Ebert
Summary: Targeted protein degradation, specifically degrading GSPT1, shows promise in cancer treatment, particularly acute myeloid leukemia. The study reveals the mechanism of GSPT1 degradation leading to impaired translation termination, activation of the integrated stress response, and cell death. The identification of key amino acids preventing GSPT1 degradation in mice and the efficacy of GSPT1-degrading drugs in vivo highlight the potential for cancer therapy.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Biochemistry & Molecular Biology
Justin T. Cruite, Geoffrey P. Dann, Jianwei Che, Katherine A. Donovan, Silas Ferrao, Scott B. Ficarro, Eric S. Fischer, Nathanael S. Gray, Fidel Huerta, Nikki R. Kong, Hu Liu, Jarrod A. Marto, Rebecca J. Metivier, Breanna L. Zerfas, Lyn H. Jones
Summary: This study demonstrates the rational targeting of a specific histidine residue in a protein binding site using sulfonyl exchange chemistry. Through structure-based drug design, potent covalent inhibitors and a labeling strategy were developed for the cereblon E3 ubiquitin ligase complex. This research expands the synthetic biology toolkit for site-selective protein modifications and contributes to the field of targeted protein degradation.
RSC CHEMICAL BIOLOGY
(2022)
Article
Oncology
Brandon J. Aubrey, Jevon A. Cutler, Wallace Bourgeois, Katherine A. Donovan, Shengqing Gu, Charlie Hatton, Sarah Perlee, Florian Perner, Homa Rahnamoun, Alexandra C. P. Theall, Jill A. Henrich, Qian Zhu, Radostaw P. Nowak, Young Joon Kim, Salma Parvin, Anjali Cremer, Sarah Naomi Olsen, Nicholas A. Eleuteri, Yana Pikman, Gerard M. McGeehan, Kimberly Stegmaier, Anthony Letai, Eric S. Fischer, X. Shirley Liu, Scott A. Armstrong
Summary: The combination targeting of IKAROS and MENIN is an effective therapeutic strategy for AML, disrupting leukemogenic transcriptional networks and resulting in synergistic killing of leukemia cells.
