The Cysteinome of Protein Kinases as a Target in Drug Development

Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping

(2017) Michael Juchum et al.   JOURNAL OF MEDICINAL CHEMISTRY

Determining Cysteines Available for Covalent Inhibition Across the Human Kinome

(2017) Zheng Zhao et al.   JOURNAL OF MEDICINAL CHEMISTRY

Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3

(2017) Felix Muth et al.   JOURNAL OF MEDICINAL CHEMISTRY

Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans

(2017) Atli Thorarensen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site

(2017) Marcel Günther et al.   JOURNAL OF MEDICINAL CHEMISTRY

Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes

(2017) Qian Zhao et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Targeting EGFR T790M mutation in NSCLC: From biology to evaluation and treatment

(2017) Antonio Passaro et al.   PHARMACOLOGICAL RESEARCH

Fluorescence polarization-based assays for detecting compounds binding to inactive c-Jun N-terminal kinase 3 and p38α mitogen-activated protein kinase

(2016) Francesco Ansideri et al.   ANALYTICAL BIOCHEMISTRY

Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant

(2016) Marcel Günther et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Targeted Covalent Inhibitors for Drug Design

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

The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations

(2016) Weiguo Zhang et al.   CANCER RESEARCH

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation–Positive Non–Small Cell Lung Cancer

(2016) Sean Khozin et al.   CLINICAL CANCER RESEARCH

A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma

(2016) Daniel W. Bowles et al.   Clinical Colorectal Cancer

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

Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3

(2016) Alvin Kung et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Proteome-wide covalent ligand discovery in native biological systems

(2016) Keriann M. Backus et al.   NATURE

Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors

(2016) Yong Jia et al.   NATURE

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

(2016) Tinghu Zhang et al.   Nature Chemical Biology

Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling

(2016) Geoffrey A Smith et al.   Nature Chemical Biology

I-SPY 2 — A Glimpse of the Future of Phase 2 Drug Development?

(2016) David Harrington et al.   NEW ENGLAND JOURNAL OF MEDICINE

Development of small molecules targeting the pseudokinase Her3

(2015) Sang Min Lim et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Identification and Characterization of an Irreversible Inhibitor of CDK2

(2015) Elizabeth Anscombe et al.   CHEMISTRY & BIOLOGY

Designing Irreversible Inhibitors-Worth the Effort?

(2015) Concepción González-Bello   ChemMedChem

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

Development of Selective Covalent Janus Kinase 3 Inhibitors

(2015) Li Tan et al.   JOURNAL OF MEDICINAL CHEMISTRY

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

(2015) James Chih-Hsin Yang et al.   LANCET ONCOLOGY

Prolonged and tunable residence time using reversible covalent kinase inhibitors

(2015) J Michael Bradshaw et al.   Nature Chemical Biology

The ins and outs of selective kinase inhibitor development

(2015) Susanne Müller et al.   Nature Chemical Biology

Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine

(2015) Ting Dong et al.   Nature Communications

First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway

(2015) M. Hagel et al.   Cancer Discovery

Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

(2015) Eric R. Goedken et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Selective Inhibition of Mutant Ras Protein through Covalent Binding

(2014) Joachim Rudolph et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Activation of Inflammasomes by Agents Causing Idiosyncratic Skin Reactions: A Possible Biomarker

(2014) J. Kyle Weston et al.   CHEMICAL RESEARCH IN TOXICOLOGY

Design and Synthesis of Tricyclic JAK3 Inhibitors with Picomolar Affinities as Novel Molecular Probes

(2014) Matthias Gehringer et al.   ChemMedChem

Recently targeted kinases and their inhibitors—the path to clinical trials

(2014) Stefan Knapp et al.   CURRENT OPINION IN PHARMACOLOGY

Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor

(2014) M. Raymond V. Finlay et al.   JOURNAL OF MEDICINAL CHEMISTRY

Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis

(2014) Shyam Krishnan et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

(2014) Nicholas Kwiatkowski et al.   NATURE

A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics

(2014) Apirat Chaikuad et al.   Nature Chemical Biology

A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors

(2014) Bryan R Lanning et al.   Nature Chemical Biology

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

(2014) Li Tan et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer

(2014) D. A. E. Cross et al.   Cancer Discovery

Developing Irreversible Inhibitors of the Protein Kinase Cysteinome

(2013) Qingsong Liu et al.   CHEMISTRY & BIOLOGY

Afatinib: First Global Approval

(2013) Rosselle T. Dungo et al.   DRUGS

The anti-inflammatory compound BAY-11-7082 is a potent inhibitor of protein tyrosine phosphatases

(2013) Navasona Krishnan et al.   FEBS Journal

Discovery of a Potent and Isoform-Selective Targeted Covalent Inhibitor of the Lipid Kinase PI3Kα

(2013) Mariana Nacht et al.   JOURNAL OF MEDICINAL CHEMISTRY

A Toxicity Risk Index, An Index for Warning Idiosyncratic Drug Toxicity

(2013) Miyoshi Morimoto et al.   JOURNAL OF PHARMACEUTICAL SCIENCES

Electrophilic Fragment-Based Design of Reversible Covalent Kinase Inhibitors

(2013) Rand M. Miller et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

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

(2013) Jonathan M. Ostrem et al.   NATURE

Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

(2013) A. O. Walter et al.   Cancer Discovery

A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer

(2012) Martin Schuler et al.   BREAST CANCER RESEARCH AND TREATMENT

Discovery of Potent and Selective Covalent Inhibitors of JNK

(2012) Tinghu Zhang et al.   CHEMISTRY & BIOLOGY

Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial

(2012) Vincent A Miller et al.   LANCET ONCOLOGY

Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles

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

Pharmacokinetic characterization of a natural product–inspired novel MEK1 inhibitor E6201 in preclinical species

(2011) Vipul Kumar et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

Cysteine Mapping in Conformationally Distinct Kinase Nucleotide Binding Sites: Application to the Design of Selective Covalent Inhibitors

(2011) Emeline Leproult et al.   JOURNAL OF MEDICINAL CHEMISTRY

Irreversible Nek2 Kinase Inhibitors with Cellular Activity

(2011) Jeffrey C. Henise et al.   JOURNAL OF MEDICINAL CHEMISTRY

Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity

(2011) Candice E Paulsen et al.   Nature Chemical Biology

The resurgence of covalent drugs

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

In Vivo Efficacy of Natural Product-Inspired Irreversible Kinase Inhibitors

(2010) Sofia Barluenga et al.   CHEMBIOCHEM

A Structure-Guided Approach to Creating Covalent FGFR Inhibitors

(2010) Wenjun Zhou et al.   CHEMISTRY & BIOLOGY

The (un)targeted cancer kinome

(2010) Oleg Fedorov et al.   Nature Chemical Biology

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

(2010) L. A. Honigberg et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Chemical Modification of Proteins at Cysteine: Opportunities in Chemistry and Biology

(2009) Justin M. Chalker et al.   Chemistry-An Asian Journal

A Zone Classification System for Risk Assessment of Idiosyncratic Drug Toxicity Using Daily Dose and Covalent Binding

(2009) S. Nakayama et al.   DRUG METABOLISM AND DISPOSITION

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

(2009) Wenjun Zhou et al.   NATURE

Molecular modeling and crystal structure of ERK2–hypothemycin complexes

(2008) Giulio Rastelli et al.   JOURNAL OF STRUCTURAL BIOLOGY

17-Acetoxyjolkinolide B irreversibly inhibits IκB kinase and induces apoptosis of tumor cells

(2008) Shou-Sheng Yan et al.   MOLECULAR CANCER THERAPEUTICS

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

(2008) D Li et al.   ONCOGENE

Idiosyncratic Drug Reactions: Past, Present, and Future

(2007) Jack Uetrecht   CHEMICAL RESEARCH IN TOXICOLOGY