Drug Discovery Digest

Kinetic Modeling of Covalent Inhibition: Effects of Rapidly Fluctuating Intermediate States

Covalent Modifiers

JUNE 2, 2025

Kyle Ghaby, Benot Roux bioRxiv 2025.05.28.656658; doi: [link] There is increasing interest in the discovery of small-molecule inhibitors that form covalent bonds with their targets for therapeutic applications. Nevertheless, identifying clear rational design principles remains challenging because the action of these molecules cannot be understood as common noncovalent inhibitors.

Small Molecule

Use of new approach methodology for hepatic safety assessment of covalent inhibitor drug candidates

Covalent Modifiers

MAY 28, 2025

Sara Amberntsson, Alison J Foster, Bhavik Chouhan, Stephen Wilkinson, Stephanie Harlfinger, Graham Smith, Jason G Kettle, Michael Niedbala, Stefan Kavanagh, Dominic P Williams Toxicology Research , 2025, 14, 3, tfaf054, [link] Interest in inhibiting target proteins through covalent binding mechanisms has increased in the last decade due to the potential for beneficial pharmacological properties.

Drugs

Drugs Treatment Research Marketing

Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers

Covalent Modifiers

MAY 27, 2025

Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C. Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyov, Dirk Scharn, Mark A. Pearson, Johannes Popow, Anna C. Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L. Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V.

Clinical Development

Clinical Development Therapies

Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitor

Covalent Modifiers

MAY 25, 2025

Dandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Journal of Medicinal Chemistry , 2025 [link] Fibroblast growth factor receptors (FGFRs) represent promising therapeutic targets in various malignancies, yet the clinical application of FGFR covalent inhibitors has been impeded by several significant challenges, including unquantifiable target engagement, undefined off-target effects, and the emergence of drug

Drugs

Discovery of a Novel Serine-Targeting Covalent Inhibitor against HCES2A for Treating Drug-induced Diarrhea and Ulcerative Colitis

Covalent Modifiers

MAY 23, 2025

Danyang Hu, Hairong Zeng, Wenxuan Li, Ya Zhang, Xiaoqian Chi, Xiaoyu Liu, Haijing Zhang, Guangbo Ge, Xiaozhen Jiao, and Ping Xie Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedchem.5c00563 Mammalian carboxylesterases play an important role in the hydrolysis of both endogenous substrates and xenobiotics bearing ester or amide bond(s). We previously reported that bysspectin A and its derivative LC-20W were potent reversible hCES2A inhibitors.

Drugs

Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30

Covalent Modifiers

MAY 18, 2025

Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka & Malte Gersch Nat Struct Mol Biol , 2025 [link] The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinsons disease.

Engineering

Engineering Regulations Small Molecule Clinical Trials

Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine

Covalent Modifiers

MAY 16, 2025

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).

Small Molecule

Small Molecule Screening Hits

Discovery of Carbodiimide Warheads to Selectively and Covalently Target Aspartic Acid in KRASG12D

Covalent Modifiers

MAY 8, 2025

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.

Drugs

Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads

Covalent Modifiers

MAY 7, 2025

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.

DNA

DNA Small Molecule Therapies Drugs

Glecirasib, a potent and selective covalent KRAS G12C inhibitor exhibiting synergism 2 with cetuximab or SHP2 inhibitor JAB-3312

Covalent Modifiers

MAY 2, 2025

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.

Biochemical Assays

Biochemical Assays Clinical Trials Trials Treatment

Discovery and Optimization of a Covalent AKR1C3 Inhibitor

Covalent Modifiers

APRIL 27, 2025

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.

Cell Biology

DCAF16-Based Covalent Degradative Handles for the Modular Design of Degraders

Covalent Modifiers

APRIL 26, 2025

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.

Targeted Protein Degradation

Targeted Protein Degradation DNA Disease

Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Identify Covalent TLCD1 Inhibitors

Covalent Modifiers

APRIL 25, 2025

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

Discovery and Optimization of a Covalent AKR1C3 Inhibitor

Covalent Modifiers

APRIL 25, 2025

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

Cell Biology

Discovery of RNA-Reactive Small Molecules Guides Design of Electrophilic Modules for RNA-Specific Covalent Binders

Covalent Modifiers

APRIL 24, 2025

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.

Small Molecule

Small Molecule RNA DNA Drugs

Identification of a phenyl ester covalent inhibitor of caseinolytic protease and analysis of the ClpP1P2 inhibition in mycobacteria

Covalent Modifiers

APRIL 20, 2025

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.

Small Molecule

Small Molecule Drugs Research

Substrate Trapping in Polyketide Synthase Thioesterase Domains: Structural Basis for Macrolactone Formation

Covalent Modifiers

APRIL 13, 2025

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.

Engineering

Engineering Production Drugs

Covalent Modification of Glutamic Acid Inspired by HaloTag Technology

Covalent Modifiers

APRIL 13, 2025

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.

Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding

Covalent Modifiers

APRIL 12, 2025

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.

Drugs

Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis

Covalent Modifiers

APRIL 9, 2025

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.

Production

A predictive model for thiol reactivity of N-heteroaryl α-methylene–γ-lactams—a medicinally relevant covalent reactive group

Covalent Modifiers

APRIL 7, 2025

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.

Drugs

Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance

Covalent Modifiers

APRIL 4, 2025

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.

Drugs

Size-Dependent Target Engagement of Covalent Probes

Covalent Modifiers

APRIL 2, 2025

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).

O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells

Covalent Modifiers

APRIL 1, 2025

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.

Drug Development

Drug Development Drugs

State-of-the-art covalent virtual screening with AlphaFold3

Covalent Modifiers

MARCH 24, 2025

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.

Research

Methods for Kinetic Evaluation of Reversible Covalent Inhibitors from Time-Dependent IC50 Data

Covalent Modifiers

MARCH 24, 2025

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

Drugs

Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition

Covalent Modifiers

MARCH 18, 2025

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.

Pharmacokinetics

Pharmacokinetics DNA

Structure-based development of a covalent inhibitor targeting Streptococcus pyogenes over Staphylococcus aureus sortase A

Covalent Modifiers

MARCH 18, 2025

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.

Comprehensive Characterization of Bruton’s Tyrosine KinaseInhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

Covalent Modifiers

MARCH 16, 2025

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.

FDA

FDA Therapies Drugs

Rational Design of Stapled Covalent Peptide Modifiers of Oncoprotein E6 from Human Papillomavirus

Covalent Modifiers

MARCH 14, 2025

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.

Regulations

Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor

Covalent Modifiers

MARCH 8, 2025

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

Production

Production Disease

Morita–Baylis–Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands

Covalent Modifiers

MARCH 3, 2025

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.

Drugs

Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid

Covalent Modifiers

MARCH 1, 2025

Guang-Hao Niu, Wan-Chi Hsiao, Po-Hsun Lee, Li-Guo Zheng, Yu-Shao Yang, Wei-Cheng Huang, Chih-Chien Hsieh, Tai-Yu Chiu, Jing-Ya Wang, Ching-Ping Chen, Chen-Lung Huang, May-Su You, Yi-Ping Kuo, Chien-Ming Wang, Zhi-Hong Wen, Guann-Yi Yu, Chiung-Tong Chen, Ya-Hui Chi, Chun-Wei Tung, Shu-Ching Hsu, Teng-Kuang Yeh, Ping-Jyun Sung, Mingzi M. Zhang, and Lun Kelvin Tsou Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedchem.4c02665 Pharmacological inhibition of the cGAS-STING-controlled innate im

Disease

Disease Treatment

Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers

Covalent Modifiers

FEBRUARY 25, 2025

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.

Clinical Trials

Clinical Trials Treatment Trials

Identification of Covalent Cyclic Peptide Inhibitors Targeting Protein–Protein Interactions Using Phage Display

Covalent Modifiers

FEBRUARY 25, 2025

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.

Metabolic Stability

Metabolic Stability Virus Disease Drugs

Site-specific activation of the proton pumpinhibitor rabeprazole by tetrathiolate zinccentres

Covalent Modifiers

FEBRUARY 21, 2025

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

Drugs

Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Identify Covalent TLCD1 Inhibitors

Covalent Modifiers

FEBRUARY 20, 2025

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.

Covalent-Allosteric Inhibitors: Do We Get the Best of Both Worlds?

Covalent Modifiers

FEBRUARY 13, 2025

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.

Drugs

Site-Specific Molecular Glues for the 14-3-3/Tau pS214 ProteinProtein Interaction via Reversible Covalent Imine Tethering

Covalent Modifiers

FEBRUARY 10, 2025

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

Biophysical Assays

Biophysical Assays Small Molecule Engineering Regulations

Structural Basis for Substrate Binding, Catalysis and Inhibition of Breast Cancer Target Mitochondrial Creatine Kinase by Covalent Inhibitor via Cryo-EM

Covalent Modifiers

FEBRUARY 6, 2025

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.

Total syntheses of cyclohelminthol I–IV reveal a new cysteine-selective covalent reactive group

Covalent Modifiers

JANUARY 30, 2025

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.

Science

Science Treatment Production Drugs

Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations

Covalent Modifiers

JANUARY 30, 2025

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.

Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer

Covalent Modifiers

JANUARY 21, 2025

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

Clinical Trials

Clinical Trials Treatment Trials

Covalent Plant Natural Product that Potentiates Antitumor Immunity

Covalent Modifiers

JANUARY 13, 2025

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

Production

Production Small Molecule Therapies

Covalent Modifiers

Kinetic Modeling of Covalent Inhibition: Effects of Rapidly Fluctuating Intermediate States

Use of new approach methodology for hepatic safety assessment of covalent inhibitor drug candidates

Trending Sources

Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers

Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitor

Discovery of a Novel Serine-Targeting Covalent Inhibitor against HCES2A for Treating Drug-induced Diarrhea and Ulcerative Colitis

Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30

Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine

Discovery of Carbodiimide Warheads to Selectively and Covalently Target Aspartic Acid in KRASG12D

Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads

Glecirasib, a potent and selective covalent KRAS G12C inhibitor exhibiting synergism 2 with cetuximab or SHP2 inhibitor JAB-3312

Discovery and Optimization of a Covalent AKR1C3 Inhibitor

DCAF16-Based Covalent Degradative Handles for the Modular Design of Degraders

Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Identify Covalent TLCD1 Inhibitors

Discovery and Optimization of a Covalent AKR1C3 Inhibitor

Discovery of RNA-Reactive Small Molecules Guides Design of Electrophilic Modules for RNA-Specific Covalent Binders

Identification of a phenyl ester covalent inhibitor of caseinolytic protease and analysis of the ClpP1P2 inhibition in mycobacteria

Substrate Trapping in Polyketide Synthase Thioesterase Domains: Structural Basis for Macrolactone Formation

Covalent Modification of Glutamic Acid Inspired by HaloTag Technology

Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding

Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis

A predictive model for thiol reactivity of N-heteroaryl α-methylene–γ-lactams—a medicinally relevant covalent reactive group

Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance

Size-Dependent Target Engagement of Covalent Probes

O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells

State-of-the-art covalent virtual screening with AlphaFold3

Methods for Kinetic Evaluation of Reversible Covalent Inhibitors from Time-Dependent IC50 Data

Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition

Structure-based development of a covalent inhibitor targeting Streptococcus pyogenes over Staphylococcus aureus sortase A

Comprehensive Characterization of Bruton’s Tyrosine KinaseInhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

Rational Design of Stapled Covalent Peptide Modifiers of Oncoprotein E6 from Human Papillomavirus

Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor

Morita–Baylis–Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands

Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid

Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers

Identification of Covalent Cyclic Peptide Inhibitors Targeting Protein–Protein Interactions Using Phage Display

Site-specific activation of the proton pumpinhibitor rabeprazole by tetrathiolate zinccentres

Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Identify Covalent TLCD1 Inhibitors

Covalent-Allosteric Inhibitors: Do We Get the Best of Both Worlds?

Site-Specific Molecular Glues for the 14-3-3/Tau pS214 ProteinProtein Interaction via Reversible Covalent Imine Tethering

Structural Basis for Substrate Binding, Catalysis and Inhibition of Breast Cancer Target Mitochondrial Creatine Kinase by Covalent Inhibitor via Cryo-EM

Total syntheses of cyclohelminthol I–IV reveal a new cysteine-selective covalent reactive group

Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations

Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer

Covalent Plant Natural Product that Potentiates Antitumor Immunity

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