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A.E. Maciag,Y. Yang,A.K. Sharma,D.M. Turner,C.J. DeHart,H. Abdelkarim,L. Fan,B.P. Smith,V. Kumari,M. Dyba,M. Rigby,J.A. Castillo Badillo,L. Adams,L. Fornelli,S. Fox,A. Brafman,T. Turbyville,W. Gillette,S. Messing,[.]& F. McCormick, Proc. Natl. Acad. Sci. 2025 122 (19) e2410766122, [link] RAS is the most frequently mutated oncogene in cancer. RAS proteins show high sequence similarities in their G-domains but are significantly different in their C-terminal hypervariable regions (HVR).
Ludovica S. Sirocchi, Maximilian Scharnweber, Sarah Oberndorfer, Gabriella Siszler, Krzysztof M. Zak, Klaus Rumpel, Ralph A. Neumller, and Birgit Wilding Journal of the American Chemical Society 2025 147 (18), 15787-15795 DOI: 10.1021/jacs.5c03562 Targeted covalent inhibitors are known to be successful therapeutics used in various indications. Covalent drugs typically target cysteine, as cysteine is well suited due to its high nucleophilicity.
Xinyuan Wu, Jiayi Pan, Rufeng Fan, Yiwei Zhang, Chao Wang, Guoliang Wang, Jiaxiang Liu, Mengqing Cui, Jinfeng Yue, Rui Jin, Zhiqiang Duan, Mingyue Zheng, Lianghe Mei, Lu Zhou, Minjia Tan, Jing Ai, and Xiaojie Lu Journal of the American Chemical Society 2025 147 (18), 15469-15481 DOI: 10.1021/jacs.5c01712 Covalent small molecule drugs have emerged as a crucial support in precision therapy due to their high selectivity and robust potency.
Wang, P., Sun, X., He, X., Kang, D., Liu, X., Liu, D., Li, A., Yang, G., Lin, Y., Li, S., Wang, Y., & Wang, Y. Cancer research communications , 2025 [link] Clinical studies have demonstrated the antitumor efficacy of covalent KRAS G12C inhibitors in treating advanced/metastatic cancers. In the current study, we report the preclinical characteristics of a specific KRAS p.G12C covalent inhibitor, glecirasib.
R. Justin Grams, Wesley J. Wolfe, Robert J. Seal, James Veccia, and Ku-Lung Hsu Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedchem.5c00050 Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the AKR superfamily of enzymes that metabolize androgen, estrogen, and prostaglandin substrates that drive proliferation in hormone-dependent cancers.
Lauren M Orr, Sydney J Tomlinson, Hannah R Grupe, Melissa Lim, Emily Ho, Halime Yilmaz, Grace Zhou, Barbara Leon, James A Olzmann, Daniel K Nomura bioRxiv 2025.04.25.650514; doi: [link] Targeted protein degradation (TPD) is a powerful strategy for targeting and eliminating disease-causing proteins. While heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) are more modular, the rational design of monovalent or molecular glue degraders remains challenging.
Hayden A. Sharma, Michael Bielecki, Meredith A. Holm, Ty M. Thompson, Yue Yin, Jacob B. Cravatt, Timothy B. Ware, Alex Reed, Molhm Nassir, Tamara El-Hayek Ewing, Bruno Melillo, J. Fernando Bazan, Phil S. Baran, and Benjamin F. Cravatt Journal of the American Chemical Society 2025 DOI: 10.1021/jacs.5c01944 Activity-based protein profiling (ABPP) of stereoisomerically defined sets of electrophilic compounds (stereoprobes) offers a versatile way to discover covalent ligands for proteins in native b
R. Justin Grams, Wesley J. Wolfe, Robert J. Seal, James Veccia, and Ku-Lung Hsu Journal of Medicinal Chemistry 2025 [link] Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the AKR superfamily of enzymes that metabolize androgen, estrogen, and prostaglandin substrates that drive proliferation in hormone-dependent cancers. Interest in developing selective inhibitors has produced tool compounds for the inactivation or degradation of AKR1C3 with varying degrees of selectivity among the
Noah A. Springer, Patrick R. A. Zanon, Amirhossein Taghavi, Kisu Sung, Matthew D. Disney bioRxiv 2025.04.22.649986; doi: [link] RNA is a key drug target that can be modulated by small molecules, however covalent binders of RNA remain largely unexplored. Using a high-throughput mass spectrometry screen of 2,000 electrophilic compounds, we identified ligands that react with RNA in a binding-dependent manner.
Genhui Xiao, Yumeng Cui, Liangliang Zhou, Chuya Niu, Bing Wang, Jinglan Wang, Shaoyang Zhou, Miaomiao Pan, Chi Kin Chan, Yan Xia, Lan Xu, Yu Lu, Shawn Chen mLife , 2025 DOI: [link] The caseinolytic protease complex ClpP1P2 is crucial for protein homeostasis in mycobacteria and stress response and virulence of the pathogens. Its role as a potential drug target for combating tuberculosis (TB) has just begun to be substantiated in drug discovery research.
Tyler M. McCullough, Vishakha Choudhary, David L. Akey, Meredith A. Skiba, Steffen M. Bernard, Jeffrey D. Kittendorf, Jennifer J. Schmidt, David H. Sherman, and Janet L. Smith ACS Catalysis 2024 14 (16), 12551-12563 DOI: 10.1021/acscatal.4c03637 Emerging antibiotic resistance requires continual improvement in the arsenal of antimicrobial drugs, especially the critical macrolide antibiotics.
Waldmann H, Zhang R, liu J, Gasper R, Janning P. ChemRxiv. 2025 doi:10.26434/chemrxiv-2025-70x40. [link] For targeted covalent protein modification at low reactivity aspartates and glutamates, new methods are in high demand. Inspired by the HaloTag technology we have developed a new technique which employs a reaction between chloroalkane-functionalised ligands and a specific glutamate residue.
Pasquale A. Morese, Ayaz Ahmad, Mathew P. Martin, Richard A. Noble, Sara Pintar, Lan Z. Wang, Shangze Xu, Andrew Lister, Richard A. Ward, Agnieszka K. Bronowska, Martin E. M. Noble, Hannah L. Stewart & Michael J. Waring Commun Chem 8 , 111 (2025). [link] The discovery of targeted covalent inhibitors is of increasing importance in drug discovery.
Dennis H. Kim and Watson J. Lees Biochemistry 2025 DOI: 10.1021/acs.biochem.4c00522 The antibiotic fosfomycin is an epoxy-phosphonate natural product with a broad spectrum of antibacterial activity and distinct mechanism of action that has been in clinical use for 50 years. Fosfomycin is an irreversible covalent inhibitor of UDP-GlcNAc enolpyruvyl transferase (MurA), which catalyzes the first committed step in bacterial peptidoglycan biosynthesis.
Meehan, M.; Scofield, G.; Stahl, C.; Wolfe, J.; Horne, W. S.; Liu, P.; Brummond, K. ChemRxiv 2025. [link] Herein, we present a systematic study on the effects of electronically diverse heteroarenes on the rate of glutathione (GSH) addition to novel N-heteroaryl methylene-lactam covalent reactive groups (CRGs). Despite their unique electronic and drug-like properties, heteroarenes have not been extensively studied as handles for systematically tuning the reactivity of CRGs.
Amanda L. Waterbury, Jonatan Caroli, Olivia Zhang, Paloma R. Tuttle, Chao Liu, Jiaming Li, Ji Sung Park, Samuel M. Hoenig, Marco Barone, Airi Furui, Andrea Mattevi & Brian B. Liau Nat Commun 16 , 3156 (2025). [link] Chromatin modifiers often work in concert with transcription factors (TFs) and other complex members, where they can serve both enzymatic and scaffolding functions.
Lszl Petri, Ronen Gabizon, Gyrgy G. Ferenczy, Nikolett Pczka, Attila Egyed, Pter brnyi-Balogh, Tams Takcs, and Gyrgy M. Keser Journal of Medicinal Chemistry 2025 68 (6), 6616-6632 DOI: 10.1021/acs.jmedchem.5c00017 Labeling proteins with covalent ligands is finding increasing use in proteomics applications, including identifying nucleophilic residues amenable for labeling and in the development of targeted covalent inhibitors (TCIs).
Huan Ling, Lin Li, Liping Duan, Weixue Huang, Jiangnan Zheng, Shijie Zhang, Xinling Li, Xiaorong Qiu, Yang Zhou, Nan Ma, Xiaomei Ren, Jinwei Zhang, Zhen Wang, Yujun Zhao, Ruijun Tian, Zhi-Min Zhang, and Ke Ding Journal of the American Chemical Society 2025 DOI: 10.1021/jacs.4c18006 Lysine residue represents an attractive site for covalent drug development due to its high abundance (5.6%) and critical functions.
Yoav Shamir, Nir London bioRxiv 2025.03.19.642201; doi: [link] Recent years have seen an explosion in the prominence of covalent inhibitors as research and therapeutic tools. However, a lag in application of computational methods for covalent docking slows progress in this field. AI models such as AlphaFold3 have shown accuracy in ligand pose prediction but were never assessed for virtual screening.
L. Mader and J. W. Keillor, RSC Med. Chem., 2025 DOI: 10.1039/D5MD00050E Potent reversible covalent inhibitors are often slow in establishing their covalent modification equilibrium, resulting in time-dependent inhibition. While these inhibitors are commonly assessed using IC50 values, there are no methods available to analyze their time-dependent IC50 data to provide their inhibition (Kiand Ki*) and covalent modification rate (k5and k6) constants, leading to difficulty in accurately ranking dru
Jianzhang Yang, Yu Chang, Kaijie Zhou, Weixue Huang, Jean Ching-Yi Tien, Pujuan Zhang, Wenyan Liu, Licheng Zhou, Yang Zhou, Xiaomei Ren, Rahul Mannan, Somnath Mahapatra, Yuping Zhang, Rudana Hamadeh, Grafton Ervine, Zhen Wang, George Xiaoju Wang, Arul M. Chinnaiyan, and Ke Ding J. Med. Chem. 2025 [link] Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate cancer (CRPC) and other human cancers.
Hailing Zhou, Ziqi Yuan, Xiang-Na Guan, Chuan Yue, Wei Wu, Lefu Lan, Jianhua Gan, Tao Zhang, Cai-Guang Yang Chemistry. 2025 [link] Sortase A (SrtA), a cysteine transpeptidase critical for surface protein anchoring in Gram-positive pathogens, represents an attractive antivirulence target. While covalent SrtA inhibitors show therapeutic potential, existing compounds lack species selectivity.
Antonia C. Darragh, Andrew M. Hanna, Justin H. Lipner, Alastair J. King, Nicole B. Servant, and Mirza Jahic ACS Pharmacol. Transl. Sci. 2025 [link] Uncovering a drugs mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether.
ACS Chem. Biol. 2025 [link] Human Papillomavirus (HPV) is linked to multiple cancers, most significantly cervical cancer, for which HPV infection is associated with nearly all cases. Essential to the oncogenesis of HPV is the function of the viral protein E6 and its role in degrading the cell cycle regulator p53. Degradation of p53, and the resultant loss of cell cycle control, is mediated by E6 recruitment of the E3 ubiquitin ligase E6AP and subsequent ubiquitination of p53.
Beatrice Noce, Sara Marchese, Marta Massari, Chiara Lambona, Joana Reis, Francesco Fiorentino, Alessia Raucci, Rossella Fioravanti, Mariana Castela, Alessandro Mormino, Stefano Garofalo, Cristina Limatola, Lorenzo Basile, Andrea Gottinger, Claudia Binda, Andrea Mattevi, Antonello Mai, and Sergio Valente Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedchem.4c02644 NADPH oxidases (NOXs) are enzymes dedicated to reactive oxygen species (ROS) production and are implicated in cancer, neuroin
Marco Paolino, Giusy Tassone, Paolo Governa, Mario Saletti, Matteo Lami, Riccardo Carletti, Filippo Sacchetta, Cecilia Pozzi, Maurizio Orlandini, Fabrizio Manetti, Massimo Olivucci, and Andrea Cappelli ACS Medicinal Chemistry Letters 2025 DOI: 10.1021/acsmedchemlett.4c00479 The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development of innovative drugs.
James Cregg, Kristof Pota, Aidan C. A. Tomlinson, Jason Yano, Abby Marquez, Yang Liu, Christopher J. Schulze, Kyle J. Seamon, Matthew Holderfield, Xing Wei, Yongxian Zhuang, Yu Chi Yang, Jingjing Jiang, Yue Huang, Ruiping Zhao, Yun Ling, Zhican Wang, Michael Flagella, Zhengping Wang, Mallika Singh, John E. Knox, Robert Nichols, David Wildes, Jacqueline A.
Sijie Wang, Franco F. Faucher, Matilde Bertolini, Heeyoung Kim, Bingchen Yu, Li Cao, Katharina Roeltgen, Scott Lovell, Varun Shanker, Scott D. Boyd, Lei Wang, Ralf Bartenschlager, and Matthew Bogyo Journal of the American Chemical Society 2025 DOI: 10.1021/jacs.4c15843 Peptide macrocycles are promising therapeutics for a variety of disease indications due to their overall metabolic stability and potential to make highly selective binding interactions with targets.
Teresa Marker, Raphael R. Steimbach, Cecilia Perez-Borrajero, Marcin Luzarowski, Eric Hartmann, Sibylle Schleich, Daniel Pastor-Flores, Elisa Espinet, Andreas Trumpp, Aurelio A. Teleman, Frauke Grter, Bernd Simon, Aubry K. Miller & Tobias P. Dick Nat. Chem. ( 2025 ). [link] Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by cov
Hayden A. Sharma, Michael Bielecki, Meredith A. Holm, Ty M. Thompson, Yue Yin, Jacob B. Cravatt, Timothy B. Ware, Alex Reed, Molham Nassir, Tamara El-Hayek Ewing, Bruno Melillo, J Fernando Bazan, Phil S. Baran, Benjamin F. Cravatt bioRxiv 2025.01.31.635883; doi: [link] Activity-based protein profiling (ABPP) of stereoisomerically defined sets of electrophilic compounds (stereoprobes) offers a versatile way to discover covalent ligands for proteins in native biological systems.
Charlotte M Zammit, Cory Nadel, Ying Lin, Sajjan Koirala, Patrick Ryan Potts, Daniel K Nomura bioRxiv 2025.02.12.637117; doi: [link] Androgen-independent prostate cancers, correlated with heightened aggressiveness and poor prognosis, are caused by mutations or deletions in the androgen receptor (AR) or expression of truncated variants of AR that are constitutively activated.
Hui Tao, Bo Yang, Atena Farhangian, Ke Xu, Tongtong Li, Zhong-Yin Zhang, and Jianing Li Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedchem.4c02760 Covalent-allosteric inhibitors (CAIs) may achieve the best of both worlds: increased potency, long-lasting effects, and reduced drug resistance typical of covalent ligands, along with enhanced specificity and decreased toxicity inherent in allosteric modulators.
DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggrfe, Semmy Engelen, Michael Sattler, Christian Ottmann, Peter Cossar and Luc Brunsveld RSC Med Chem 2025 [link] Protein-protein interactions (PPIs) are key regulators of various cellular processes. Modulating PPIs with small molecules has gained increasing attention in drug discovery, particularly targeting the 14-3-3 protein family, which interacts with several hundred client proteins and plays a central role in cellular net
Merve Demir,*, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko Structure, 2024 [link] Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the energy shuttle for cell growth and survival.
DOI Thomas T. Paulsen, Anders E. Kiib, Gustav J. Wrmer, Stephan M. Hacker and Thomas B. Poulsen Chemical Science, 2025 [link] Biocompatible covalent reactive groups (CRGs) play pivotal roles in several areas of chemical biology and the life sciences, including targeted covalent inhibitor design and preparation of advanced biologic drugs, such as antibodydrug conjugates.
William McCoull, Clare Thomson, Erin Braybrooke, Christina Chan, Nicola Colclough, Miguel A. Corts Gonzlez, Sabina Cosulich, Nichola L. Davies, Nicolas Floch, Ryan Greenwood, David Hargreaves, Peng Huang, Thomas A. Hunt, Tony Johnson, Peter Johnstrm, Jason G. Kettle, Mikhail Kondrashov, Demetrios H. Kostomiris, Songlei Li, Andrew Lister, Scott Martin, Darren McKerrecher, Neville McLean, J.
Benjamin C. Milgram, Deanna R. Borrelli, Natasja Brooijmans, Jack A. Henderson, Brendan J. Hilbert, Michael R. Huff, Takahiro Ito, Erica L. Jackson, Philip Jonsson, Brendon Ladd, Erin L. OHearn, Raymond A. Pagliarini, Simon A. Roberts, Sbastien Ronseaux, Darrin D. Stuart, Weixue Wang, and Angel Guzman-Perez Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedchem.4c02377 After L858R and ex19del epidermal growth factor receptor (EGFR) mutations, ex20ins mutations are the third most common cl
Misao Takemoto, Sara Delghandi, Masahiro Abo, Keiko Yurimoto, Minami Odagi, Vaibhav Pal Singh, Jun Wang, Reiko Nakagawa, Shin-ichi Sato, Yasushi Takemoto, Asmaa M. A. S. Farrag, Yoshimasa Kawaguchi, Kazuo Nagasawa, Tasuku Honjo, Kenji Chamoto, and Motonari Uesugi Journal of the American Chemical Society 2025 DOI: 10.1021/jacs.4c17837 Despite the unprecedented therapeutic potential of immune checkpoint antibody therapies, their efficacy is limited partly by the dysfunction of T cells within the c
Bryn Marie Reimer, Ernest Awoonor-Williams, Andrei A. Golosov, and Viktor Hornak Journal of Chemical Information and Modeling 2025 DOI: 10.1021/acs.jcim.4c01281 Targeted covalent inhibition is a powerful therapeutic modality in the drug discoverers toolbox. Recent advances in covalent drug discovery, in particular, targeting cysteines, have led to significant breakthroughs for traditionally challenging targets such as mutant KRAS, which is implicated in diverse human cancers.
Fangyuan Chen, Qingmei Liu, Lei Ma, Cuishi Yan, Haiman Zhang, Zhi Zhou, and Wei Yi Journal of Medicinal Chemistry 2025 68 (1), 819-831 DOI: 10.1021/acs.jmedchem.4c02803 Recent studies have identified selective peroxisome proliferator-activated receptor (PPAR) modulators, which synergistically engage in the inhibition mechanism of PPAR-Ser273 phosphorylation, as a promising approach for developing safer and more effective antidiabetic drugs.
Ferran Esteve, Jean-Louis Schmitt, Sergii Kolodych, Oleksandr Koniev, and Jean-Marie Lehn Journal of the American Chemical Society 2025 DOI: 10.1021/jacs.4c15421 SNAr reactions were remarkably accelerated using a pretargeting and activating unit based on dynamic covalent chemistry (DCvC). A Cys attack at the CF bond on the aromatic ring of salicylaldehyde derivatives was only observed upon iminium formation with a neighboring Lys residue of model small peptides.
Tomonori Tamura, Masaharu Kawano, and Itaru Hamachi Chemical Reviews 2024 DOI: 10.1021/acs.chemrev.4c00745 The term undruggable refers to proteins or other biological targets that have been historically challenging to target with conventional drugs or therapeutic strategies because of their structural, functional, or dynamic properties. Drugging such undruggable targets is essential to develop new therapies for diseases where current treatment options are limited or nonexistent.
Matthew Bogyo, Tulsi Upadhyay, Emily Woods, Stephen Ahator. Kjersti Julin, Franco Faucher, Marijn Hollander, Nichole Pedowitz, Daniel Abegg, Isabella Hammond, Ifeanyichukwu Eke, Sijie Wang, Shiyu Chen, John Bennett, Jeyun Jo, Christian Lentz, Alex Adibekian, Matthias Fellner Research Square Preprint 2025 [link] 10.21203/rs.3.rs-5494070/v1 Staphylococcus aureus is a leading cause of bacteria-associated mortality worldwide.
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