Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases

New insights into the structure and function of the pseudokinase domain in JAK2

(2013) Olli Silvennoinen et al.   BIOCHEMICAL SOCIETY TRANSACTIONS

Allosite: a method for predicting allosteric sites

(2013) Wenkang Huang et al.   BIOINFORMATICS

Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories

(2013) Ingo V. Hartung et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Structure-based discovery of cellular-active allosteric inhibitors of FAK

(2013) Naoki Tomita et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Tribbles in acute leukemia

(2013) K. L. Liang et al.   BLOOD

COP1 targets C/EBP  for degradation and induces acute myeloid leukemia via Trib1

(2013) A. Yoshida et al.   BLOOD

Oncogenic ERBB3 Mutations in Human Cancers

(2013) Bijay S. Jaiswal et al.   CANCER CELL

Developing Irreversible Inhibitors of the Protein Kinase Cysteinome

(2013) Qingsong Liu et al.   CHEMISTRY & BIOLOGY

Selective Bisubstrate Inhibitors with Sub-nanomolar Affinity for Protein Kinase Pim-1

(2013) Ramesh Ekambaram et al.   ChemMedChem

Small interfering RNA targeting ILK inhibits metastasis in human tongue cancer cells through repression of epithelial-to-mesenchymal transition

(2013) Yu Xing et al.   EXPERIMENTAL CELL RESEARCH

Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages

(2013) Takashi Satoh et al.   NATURE

Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

(2013) Georgia Hatzivassiliou et al.   NATURE

Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells

(2013) Mikko Taipale et al.   NATURE BIOTECHNOLOGY

Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases

(2013) Angela V Toms et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

ASD v2.0: updated content and novel features focusing on allosteric regulation

(2013) Zhimin Huang et al.   NUCLEIC ACIDS RESEARCH

Structure-kinetic relationship study of CDK8/CycC specific compounds

(2013) E. V. Schneider et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Structural Basis of RIP1 Inhibition by Necrostatins

(2013) Tian Xie et al.   STRUCTURE

Strategies for the Selective Regulation of Kinases with Allosteric Modulators: Exploiting Exclusive Structural Features

(2012) Zhizhou Fang et al.   ACS Chemical Biology

Clinical and radiological features of Japanese patients with a severe phenotype due toCASKmutations

(2012) Jun-ichi Takanashi et al.   AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Targeting ILK and β4 integrin abrogates the invasive potential of ovarian cancer

(2012) Yoon Pyo Choi et al.   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors

(2012) Samit K. Bhattacharya et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia

(2012) T. Yokoyama et al.   BLOOD

Exploiting protein flexibility to predict the location of allosteric sites

(2012) Alejandro Panjkovich et al.   BMC BIOINFORMATICS

A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

(2012) Joost CM Uitdehaag et al.   BRITISH JOURNAL OF PHARMACOLOGY

A Novel Approach to the Discovery of Small-Molecule Ligands of CDK2

(2012) Mathew P. Martin et al.   CHEMBIOCHEM

Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF-Pocket Allosteric Docking Site

(2012) Katrien Busschots et al.   CHEMISTRY & BIOLOGY

RAS/RAF/MEK Inhibitors in Oncology

(2012) M. Broggini   CURRENT MEDICINAL CHEMISTRY

Fragment Based Drug Design: From Experimental to Computational Approaches

(2012) A. Kumar et al.   CURRENT MEDICINAL CHEMISTRY

ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling

(2012) Jun Qin et al.   CURRENT OPINION IN CELL BIOLOGY

CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia

(2012) Hirotomo Saitsu et al.   EPILEPSIA

Discovery and characterization of novel allosteric FAK inhibitors

(2012) Misa Iwatani et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation

(2012) Ian P Salt et al.   EXPERT OPINION ON INVESTIGATIONAL DRUGS

Direct AMP-activated protein kinase activators: a review of evidence from the patent literature

(2012) Fabrizio Giordanetto et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

Discovery and Optimization of a Series of 3-(3-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: Orally Bioavailable, Selective, and Potent ATP-Independent Akt Inhibitors

(2012) Mark A. Ashwell et al.   JOURNAL OF MEDICINAL CHEMISTRY

2-(3-Oxo-1,3-diphenylpropyl)malonic Acids as Potent Allosteric Ligands of the PIF Pocket of Phosphoinositide-Dependent Kinase-1: Development and Prodrug Concept

(2012) Adriana Wilhelm et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions

(2012) Robert A. Heald et al.   JOURNAL OF MEDICINAL CHEMISTRY

Lipid Molecules Induce p38α Activation via a Novel Molecular Switch

(2012) Netanel Tzarum et al.   JOURNAL OF MOLECULAR BIOLOGY

Overexpression of integrin-linked kinase (ILK) is associated with tumor progression and an unfavorable prognosis in patients with colorectal cancer

(2012) Rui Li et al.   JOURNAL OF MOLECULAR HISTOLOGY

Engineering human MEK-1 for structural studies: A case study of combinatorial domain hunting

(2012) Christoph Meier et al.   JOURNAL OF STRUCTURAL BIOLOGY

Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl

(2012) Ralf Schneider et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

An integrin–ILK–microtubule network orients cell polarity and lumen formation in glandular epithelium

(2012) Nasreen Akhtar et al.   NATURE CELL BIOLOGY

Natural-product-derived fragments for fragment-based ligand discovery

(2012) Björn Over et al.   Nature Chemistry

Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F

(2012) Rajintha M Bandaranayake et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

A Novel Protein Kinase-Like Domain in a Selenoprotein, Widespread in the Tree of Life

(2012) Małgorzata Dudkiewicz et al.   PLoS One

Fluorophore Labeled Kinase Detects Ligands That Bind within the MAPK Insert of p38α Kinase

(2012) Matthäus Getlik et al.   PLoS One

The Raine Syndrome Protein FAM20C Is a Golgi Kinase That Phosphorylates Bio-Mineralization Proteins

(2012) Hiroyuki O. Ishikawa et al.   PLoS One

Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations

(2012) B. K. Gilsbach et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Secreted Kinase Phosphorylates Extracellular Proteins That Regulate Biomineralization

(2012) V. S. Tagliabracci et al.   SCIENCE

ILK and PRDX1 are prognostic markers in squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder

(2012) Jinghe Li et al.   TUMOR BIOLOGY

A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases

(2012) Hidehisa Iwata et al.   ACS Medicinal Chemistry Letters

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

(2012) Kenneth D. Rice et al.   ACS Medicinal Chemistry Letters

Targeting Diverse Signaling Interaction Sites Allows the Rapid Generation of Bivalent Kinase Inhibitors

(2011) Zachary B. Hill et al.   ACS Chemical Biology

Discovery of a Potential Allosteric Ligand Binding Site in CDK2

(2011) Stephane Betzi et al.   ACS Chemical Biology

Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD)

(2011) Kristofer Moffett et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

(2011) Qing Dong et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent

(2011) Yoshiaki Isshiki et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036

(2011) Wayne W. Chan et al.   CANCER CELL

The secret life of kinases: functions beyond catalysis

(2011) Jens Rauch et al.   Cell Communication and Signaling

Allosteric Regulation of Protein Kinase PKCζ by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket

(2011) Laura A. Lopez-Garcia et al.   CHEMISTRY & BIOLOGY

Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

(2011) Jingsong Yang et al.   CHEMISTRY & BIOLOGY

Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing

(2011) Oleg Fedorov et al.   CHEMISTRY & BIOLOGY

FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors

(2011) Elena Mancini et al.   EMBO JOURNAL

Targeting Energy Metabolic and Oncogenic Signaling Pathways in Triple-negative Breast Cancer by a Novel Adenosine Monophosphate-activated Protein Kinase (AMPK) Activator

(2011) Kuen-Haur Lee et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors

(2011) Timothy A. Yap et al.   JOURNAL OF CLINICAL ONCOLOGY

Phenotypic spectrum associated with CASK loss-of-function mutations

(2011) U. Moog et al.   JOURNAL OF MEDICAL GENETICS

4-Benzimidazolyl-3-Phenylbutanoic Acids As Novel Pif-Pocket-Targeting Allosteric Inhibitors of Protein Kinase PKCζ

(2011) Wolfgang Fröhner et al.   JOURNAL OF MEDICINAL CHEMISTRY

Crystal Structures of ABL-Related Gene (ABL2) in Complex with Imatinib, Tozasertib (VX-680), and a Type I Inhibitor of the Triazole Carbothioamide Class

(2011) Eidarus Salah et al.   JOURNAL OF MEDICINAL CHEMISTRY

Exploring the Binding Sites of Glycogen Synthase Kinase 3. Identification and Characterization of Allosteric Modulation Cavities

(2011) Valle Palomo et al.   JOURNAL OF MEDICINAL CHEMISTRY

Leucettines, a Class of Potent Inhibitors of cdc2-Like Kinases and Dual Specificity, Tyrosine Phosphorylation Regulated Kinases Derived from the Marine Sponge Leucettamine B: Modulation of Alternative Pre-RNA Splicing

(2011) Mansour Debdab et al.   JOURNAL OF MEDICINAL CHEMISTRY

How Does a Drug Molecule Find Its Target Binding Site?

(2011) Yibing Shan et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Too many roads not taken

(2011) Aled M. Edwards et al.   NATURE

Comprehensive analysis of kinase inhibitor selectivity

(2011) Mindy I Davis et al.   NATURE BIOTECHNOLOGY

Drug discovery and the human kinome: Recent trends

(2011) Richard Eglen et al.   PHARMACOLOGY & THERAPEUTICS

Turning a protein kinase on or off from a single allosteric site via disulfide trapping

(2011) J. D. Sadowsky et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Discovery and Characterization of Non-ATP Site Inhibitors of the Mitogen Activated Protein (MAP) Kinases

(2010) Kenneth M. Comess et al.   ACS Chemical Biology

Design and synthesis of benzoazepin-2-one analogs as allosteric binders targeting the PIF pocket of PDK1

(2010) Linyi Wei et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region

(2010) Yu Mi Ahn et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors

(2010) Michael B. Wallace et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis

(2010) T. Yokoyama et al.   BLOOD

Differential ability of Tribbles family members to promote degradation of C/EBP  and induce acute myelogenous leukemia

(2010) P. H. Dedhia et al.   BLOOD

Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding

(2010) K. Keeshan et al.   BLOOD

Pseudokinases-remnants of evolution or key allosteric regulators?

(2010) Elton Zeqiraj et al.   CURRENT OPINION IN STRUCTURAL BIOLOGY

Akt inhibitors in clinical development for the treatment of cancer

(2010) Sumanta Kumar Pal et al.   EXPERT OPINION ON INVESTIGATIONAL DRUGS

Discovery of PDK1 Kinase Inhibitors with a Novel Mechanism of Action by Ultrahigh Throughput Screening

(2010) Ekaterina V. Bobkova et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

(2010) Stephen M. Massa et al.   JOURNAL OF CLINICAL INVESTIGATION

Binding or Bending: Distinction of Allosteric Abl Kinase Agonists from Antagonists by an NMR-Based Conformational Assay

(2010) Wolfgang Jahnke et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

(2010) Jianming Zhang et al.   NATURE

The (un)targeted cancer kinome

(2010) Oleg Fedorov et al.   Nature Chemical Biology

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors

(2010) Alexandra Dusa et al.   PLoS One

Crystal Structure of Human AKT1 with an Allosteric Inhibitor Reveals a New Mode of Kinase Inhibition

(2010) Wen-I Wu et al.   PLoS One

ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

(2010) Fumin Shi et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Allosteric IGF-1R Inhibitors

(2010) Timo Heinrich et al.   ACS Medicinal Chemistry Letters

Structural analysis of an MK2–inhibitor complex: insight into the regulation of the secondary structure of the Gly-rich loop by TEI-I01800

(2009) Aiko Fujino et al.   ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY

A Missense Mutation in CASK Causes FG Syndrome in an Italian Family

(2009) Giulio Piluso et al.   AMERICAN JOURNAL OF HUMAN GENETICS

FAM20B is a kinase that phosphorylates xylose in the glycosaminoglycan–protein linkage region

(2009) Toshiyasu Koike et al.   BIOCHEMICAL JOURNAL

Characterization of the CHK1 Allosteric Inhibitor Binding Site

(2009) Darin Vanderpool et al.   BIOCHEMISTRY

Kinetic Mechanism and Inhibitor Characterization of WNK1 Kinase

(2009) Yukiko I. Yagi et al.   BIOCHEMISTRY

Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors

(2009) Thierry O. Fischmann et al.   BIOCHEMISTRY

Insights into protein kinase regulation and inhibition by large scale structural comparison

(2009) Jeyanthy Eswaran et al.   BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

(2009) C. Iverson et al.   CANCER RESEARCH

Large-Scale Structural Analysis of the Classical Human Protein Tyrosine Phosphatome

(2009) Alastair J. Barr et al.   CELL

The Design, Synthesis and Potential Utility of Fluorescence Probes that Target DFG-out Conformation of p38α for High Throughput Screening Binding Assay

(2009) Haile Tecle et al.   Chemical Biology & Drug Design

Identification of Allosteric PIF-Pocket Ligands for PDK1 using NMR-Based Fragment Screening and1H-15N TROSY Experiments

(2009) Brian J. Stockman et al.   Chemical Biology & Drug Design

Bisubstrate Inhibitors of Protein Kinases: from Principle to Practical Applications

(2009) Darja Lavogina et al.   ChemMedChem

Activated Abl kinase inhibits oncogenic transforming growth factor-β signaling and tumorigenesis in mammary tumors

(2009) Tressa M. Allington et al.   FASEB JOURNAL

Displacement Assay for the Detection of Stabilizers of Inactive Kinase Conformations

(2009) Sabine Klüter et al.   JOURNAL OF MEDICINAL CHEMISTRY

Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation

(2009) Fabio Zuccotto et al.   JOURNAL OF MEDICINAL CHEMISTRY

p38α MAP Kinase C-Terminal Domain Binding Pocket Characterized by Crystallographic and Computational Analyses

(2009) J. Jefferson P. Perry et al.   JOURNAL OF MOLECULAR BIOLOGY

An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently

(2009) J. Viaud et al.   MOLECULAR CANCER THERAPEUTICS

The Pseudoactive Site of ILK Is Essential for Its Binding to α-Parvin and Localization to Focal Adhesions

(2009) Koichi Fukuda et al.   MOLECULAR CELL

A new screening assay for allosteric inhibitors of cSrc

(2009) Jeffrey R Simard et al.   Nature Chemical Biology

Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1

(2009) Valerie Hindie et al.   Nature Chemical Biology

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

(2009) Patrick S Tarpey et al.   NATURE GENETICS

Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3

(2009) N. Jura et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Structure of the Pseudokinase VRK3 Reveals a Degraded Catalytic Site, a Highly Conserved Kinase Fold, and a Putative Regulatory Binding Site

(2009) Eric D. Scheeff et al.   STRUCTURE

2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles—O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)

(2008) Joseph S. Warmus et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

(2008) Antonella Converso et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Allosteric inhibitors of Akt1 and Akt2: Discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity

(2008) Yiwei Li et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

CASK Functions as a Mg2+-Independent Neurexin Kinase

(2008) Konark Mukherjee et al.   CELL

An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase

(2008) Sean W. Deacon et al.   CHEMISTRY & BIOLOGY

Integrin-linked kinase - essential roles in physiology and cancer biology

(2008) P. C. McDonald et al.   JOURNAL OF CELL SCIENCE

Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases

(2008) Jesus Vazquez et al.   JOURNAL OF MEDICINAL CHEMISTRY

Identification of a new JNK inhibitor targeting the JNK-JIP interaction site

(2008) J. L. Stebbins et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Four-jointed Is a Golgi Kinase That Phosphorylates a Subset of Cadherin Domains

(2008) H. O. Ishikawa et al.   SCIENCE

Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity

(2007) Zhijian Zhao et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS