10 years into the resurgence of covalent drugs

KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?

(2020) Misako Nagasaka et al.   CANCER TREATMENT REVIEWS

Axicabtagene ciloleucel CD19 CAR-T cell therapy results in high rates of systemic and neurologic remissions in ten patients with refractory large B cell lymphoma including two with HIV and viral hepatitis

(2020) Ahmed Abbasi et al.   Journal of Hematology & Oncology

Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

(2020) Xiaobo Wan et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Covalent-Fragment Screening of BRD4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites

(2020) Michael D. Olp et al.   ACS Chemical Biology

Cyanopyrrolidine Inhibitors of Ubiquitin Specific Protease 7 Mediate Desulfhydration of the Active-Site Cysteine

(2020) Charlene Bashore et al.   ACS Chemical Biology

The Frequency of Ras Mutations in Cancer

(2020) Ian A. Prior et al.   CANCER RESEARCH

Covalent fragment libraries in drug discovery

(2020) Aaron Keeley et al.   DRUG DISCOVERY TODAY

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer

(2020) Jay B. Fell et al.   JOURNAL OF MEDICINAL CHEMISTRY

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

(2020) Kirsten McAulay et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Drug–protein adducts: past, present, and future

(2020) Thomas A. Baillie   MEDICINAL CHEMISTRY RESEARCH

Crowdsourcing drug discovery for pandemics

(2020) John Chodera et al.   Nature Chemistry

Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP

(2019) Henrik Johansson et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Selective and reversible modification of kinase cysteines with chlorofluoroacetamides

(2019) Naoya Shindo et al.   Nature Chemical Biology

PKAD: a database of experimentally measured pKa values of ionizable groups in proteins

(2019) Swagata Pahari et al.   Database-The Journal of Biological Databases and Curation

Properties of FDA-approved small molecule protein kinase inhibitors

(2019) Robert Roskoski   PHARMACOLOGICAL RESEARCH

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

(2019) Elma Mons et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Covalent Inhibitors of Protein–Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues

(2019) Luca Gambini et al.   JOURNAL OF MEDICINAL CHEMISTRY

Rapid covalent-probe discovery by electrophile-fragment screening

(2019) Efrat Resnick et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

The Proteome-Wide Potential for Reversible Covalency at Cysteine

(2019) Kristine Senkane et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

A Fast Ab Initio Predictor Tool for Covalent Reactivity Estimation of Acrylamides

(2019) Ferruccio Palazzesi et al.   Journal of Chemical Information and Modeling

Systematic Studies on the Protocol and Criteria for Selecting a Covalent Docking Tool

(2019) Chang Wen et al.   MOLECULES

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

(2019) Alessandro Leonetti et al.   BRITISH JOURNAL OF CANCER

Aryl-fluorosulfate-based Lysine Covalent Pan-Inhibitors of Apoptosis Protein (IAP) Antagonists with Cellular Efficacy

(2019) Carlo Baggio et al.   JOURNAL OF MEDICINAL CHEMISTRY

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

(2019) Jude Canon et al.   NATURE

Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

(2019) Brian A. Lanman et al.   JOURNAL OF MEDICINAL CHEMISTRY

Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes

(2019) Daniel Conole et al.   Frontiers in Chemistry

Chemoproteomics-Enabled Covalent Ligand Screening Reveals ALDH3A1 as a Lung Cancer Therapy Target

(2018) Jessica L. Counihan et al.   ACS Chemical Biology

High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery

(2018) Gregory B. Craven et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

The Taxonomy of Covalent Inhibitors

(2018) Alfred Tuley et al.   BIOCHEMISTRY

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor

(2018) Matthew R. Janes et al.   CELL

Comparative Evaluation of Covalent Docking Tools

(2018) Andrea Scarpino et al.   Journal of Chemical Information and Modeling

Docking of Covalent Ligands: Challenges and Approaches

(2018) Christoph Sotriffer   Molecular Informatics

Kinase inhibitors: the road ahead

(2018) Fleur M. Ferguson et al.   NATURE REVIEWS DRUG DISCOVERY

Let K-Ras activate its own inhibitor

(2018) Alexander V. Statsyuk   NATURE STRUCTURAL & MOLECULAR BIOLOGY

The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors

(2018) Rasmus Hansen et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Let K-Ras activate its own inhibitor

(2018) Alexander V. Statsyuk   NATURE STRUCTURAL & MOLECULAR BIOLOGY

The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors

(2018) Rasmus Hansen et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Design and Characterization of Novel Covalent Bromodomain and Extra-Terminal Domain (BET) Inhibitors Targeting a Methionine

(2018) Olesya A. Kharenko et al.   JOURNAL OF MEDICINAL CHEMISTRY

Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

(2018) Elena De Vita et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments

(2018) Sandipan Roy Chowdhury et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

(2018) Matthias Gehringer et al.   JOURNAL OF MEDICINAL CHEMISTRY

Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors

(2018) Agustin Casimiro-Garcia et al.   JOURNAL OF MEDICINAL CHEMISTRY

Pharmacological targeting of RAS: Recent success with direct inhibitors

(2018) John P. O’Bryan   PHARMACOLOGICAL RESEARCH

Therapeutic Potential of Nitrogen Mustard Based Hybrid Molecules

(2018) Yiming Chen et al.   Frontiers in Pharmacology

“Inverse Drug Discovery” Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates

(2017) David E. Mortenson et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Selective lysine modification of native peptides via aza-Michael addition

(2017) Hongli Chen et al.   ORGANIC & BIOMOLECULAR CHEMISTRY

Targeted Covalent Inhibitors for Drug Design

(2016) Thomas A. Baillie   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

(2016) Dieter Brömme et al.   Expert Opinion on Drug Discovery

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

(2016) Paul A. Jackson et al.   JOURNAL OF MEDICINAL CHEMISTRY

Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors

(2016) Balyn W. Zaro et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Identification of Covalent Binding Sites Targeting Cysteines Based on Computational Approaches

(2016) Yanmin Zhang et al.   MOLECULAR PHARMACEUTICS

Proteome-wide covalent ligand discovery in native biological systems

(2016) Keriann M. Backus et al.   NATURE

Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

(2016) Gizem Akçay et al.   Nature Chemical Biology

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

(2016) P. Lito et al.   SCIENCE

Covalent tethering of fragments for covalent probe discovery

(2016) Stefan G. Kathman et al.   MedChemComm

Intrinsic reactivity profile of electrophilic moieties to guide covalent drug design: N-α-acetyl-l-lysine as an amine nucleophile

(2016) Upendra P. Dahal et al.   MedChemComm

Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

(2016) C. Zambaldo et al.   MedChemComm

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

(2016) M. P. Patricelli et al.   Cancer Discovery

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

(2015) Mingshan Niu et al.   CANCER BIOLOGY & THERAPY

Identification and Characterization of an Irreversible Inhibitor of CDK2

(2015) Elizabeth Anscombe et al.   CHEMISTRY & BIOLOGY

Identifying Drug-Target Selectivity of Small-Molecule CRM1/XPO1 Inhibitors by CRISPR/Cas9 Genome Editing

(2015) Jasper E. Neggers et al.   CHEMISTRY & BIOLOGY

FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia

(2015) R. A. de Claro et al.   CLINICAL CANCER RESEARCH

Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies

(2015) Renato A. Bauer   DRUG DISCOVERY TODAY

Systematic Study of the Glutathione (GSH) Reactivity of N-Arylacrylamides: 1. Effects of Aryl Substitution

(2015) Victor J. Cee et al.   JOURNAL OF MEDICINAL CHEMISTRY

Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls

(2015) Hezekiel Kumalo et al.   MOLECULES

The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins

(2015) Dima Kozakov et al.   Nature Protocols

The drug–target residence time model: a 10-year retrospective

(2015) Robert A. Copeland   NATURE REVIEWS DRUG DISCOVERY

Covalent docking using autodock: Two-point attractor and flexible side chain methods

(2015) Giulia Bianco et al.   PROTEIN SCIENCE

Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

(2014) Jiajia Dong et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Docking Covalent Inhibitors: A Parameter Free Approach To Pose Prediction and Scoring

(2014) Kai Zhu et al.   Journal of Chemical Information and Modeling

Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

(2014) Mark E. Flanagan et al.   JOURNAL OF MEDICINAL CHEMISTRY

A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles

(2014) Guangxin Xia et al.   JOURNAL OF MEDICINAL CHEMISTRY

Chemistry: Chemical con artists foil drug discovery

(2014) Jonathan Baell et al.   NATURE

Covalent docking of large libraries for the discovery of chemical probes

(2014) Nir London et al.   Nature Chemical Biology

Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor

(2013) Sang Min Lim et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Drug discovery considerations in the development of covalent inhibitors

(2013) Robert Mah et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Afatinib: First Global Approval

(2013) Rosselle T. Dungo et al.   DRUGS

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

(2013) Jonathan M. Ostrem et al.   NATURE

Reversible Covalent Inhibition of a Protein Target

(2012) Chang-Uk Lee et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

A Comprehensive Survey of Ras Mutations in Cancer

(2012) I. A. Prior et al.   CANCER RESEARCH

Drug discovery for a new generation of covalent drugs

(2012) Amit S Kalgutkar et al.   Expert Opinion on Drug Discovery

CovalentDock: Automated covalent docking with parameterized covalent linkage energy estimation and molecular geometry constraints

(2012) Xuchang Ouyang et al.   JOURNAL OF COMPUTATIONAL CHEMISTRY

Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

(2012) Ori Kalid et al.   JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN

Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles

(2012) Iana M Serafimova et al.   Nature Chemical Biology

An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee

(2012) John P. Huggins et al.   PAIN

Measurement and Estimation of Electrophilic Reactivity for Predictive Toxicology

(2011) Johannes A. H. Schwöbel et al.   CHEMICAL REVIEWS

Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors

(2011) Ken Coleman   CURRENT OPINION IN MICROBIOLOGY

The resurgence of covalent drugs

(2011) Juswinder Singh et al.   NATURE REVIEWS DRUG DISCOVERY

Quantitative reactivity profiling predicts functional cysteines in proteomes

(2010) Eranthie Weerapana et al.   NATURE

Covalent Modifiers: An Orthogonal Approach to Drug Design

(2009) Michele H. Potashman et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structural basis for leucine-rich nuclear export signal recognition by CRM1

(2009) Xiuhua Dong et al.   NATURE

Inhibition of the CRM1-mediated nucleocytoplasmic transport by N-azolylacrylates: Structure–activity relationship and mechanism of action

(2008) Tine Van Neck et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Disparate proteome reactivity profiles of carbon electrophiles

(2008) Eranthie Weerapana et al.   Nature Chemical Biology

BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models

(2008) D Li et al.   ONCOGENE