DOCSLIB.ORG

Protein Kinases As Drug Targets

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Methods and Principles in Medicinal Chemistry 49 Protein Kinases as Drug Targets Bearbeitet von Bert Klebl, Gerhard Müller, Michael Hamacher, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers 1st Edition 2011 2011. Buch. XXII, 374 S. Hardcover ISBN 978 3 527 31790 5 Format (B x L): 17 x 24 cm Gewicht: 914 g Weitere Fachgebiete > Technik > Verfahrenstechnik, Chemieingenieurwesen, Lebensmitteltechnik > Pharmazeutische Technologie Zu Inhaltsverzeichnis schnell und portofrei erhältlich bei Die Online-Fachbuchhandlung beck-shop.de ist spezialisiert auf Fachbücher, insbesondere Recht, Steuern und Wirtschaft. Im Sortiment finden Sie alle Medien (Bücher, Zeitschriften, CDs, eBooks, etc.) aller Verlage. Ergänzt wird das Programm durch Services wie Neuerscheinungsdienst oder Zusammenstellungen von Büchern zu Sonderpreisen. Der Shop führt mehr als 8 Millionen Produkte. j365 Index a 3-amino-6,11-dihydro-dibenzo[b,e]thiepin- A-420983 179 11-one 295 A-641593 179 3-amino-tetrahydropyrrolo[3,4-c] A-770041 179 pyrazole 217 AAL-993 177 amino-thiazolo acetanilide quinazolines 208 Abelson (Abl) kinase 74ff., 151ff., 177 AMN107 118, 170 – inhibitor 186 analogue-sensitive kinase allele (ASKA) absorption 71ff. – gastrointestinal cell 28 – application in molecular biology 76 absorption, distribution, metabolism, and anilinoquinazoline 203 excretion (ADME) issue antibody-based detection 56 – protein kinase inhibitor in early drug antihypertensive drug 90 discovery 26 antiviral activity 338 ACE (angiotensin-converting enzyme) – PCI 310, 327 inhibitor 90 antiviral target activator protein-1 (AP1) 131 – cellular protein kinase 305ff. active analogue approach (AAA) 92 ARQ197 123 acute myelogenous leukemia (AML) 116 ARRY142886 (AZD6244) 126 adenine binding region 104 ARRY438162 125 adenovirus 327 N-aryl-N0-pyrazolylurea 287 AEB071 126 ASKA kinase 71ff. AEE788 120 ASKA ligand–kinase pair AEW541/NPV-AEW541 120 – engineering 71 affinity chromatography ASKA EGFR 73 – immobilized kinase inhibitor 63 ASKA Src 72ff. – kinase inhibitor 97 AT9283 128, 220, 250 AG013736 116 ATP 94 AG024322 127 – competition 47, 102 Akt (Akt1)/ PKB (protein kinase B) 129 ATP analogues 72 Akt/PDK-/Flt3 multiple target inhibitor 117 ATP binding cassette (ABC) transporter allosteric kinase inhibitor 101 33ff. allosteric site 17 – ABCB1 (P-gp) 27ff. AlphaScreen-based Surefire technology 58 – ABCC2 36 AMG-548 292 – ABCG2 36, 119 AMG706 121 ATP binding site 91ff. 2-aminobenzimidazole 172 ATP concentration 10ff., 48 2-aminobenzoxazole 172 ATP site specificity 236 2-aminoquinazoline 176ff. ATP-competitive inhibitor 97, 147, 281 Protein Kinases as Drug Targets. Edited by B. Klebl, G. Müller, and M. Hamacher Copyright Ó 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31790-5 366j Index Aurora kinase 96, 127 – signal linearity throughout the reaction – Aurora A (AurKA, AKA) 99, 151, 175, time 12 – 196ff., 243 validation by measurement of IC50 of – Aurora B (AurKB, AKB) 175, 196ff., 243 reference inhibitor 15 – Aurora C (AKC) 196ff., 244 biomolecular interaction analysis – biological role 195f. – surface plasmon resonance (SPR)-based 19 – cancer 196 biosensor – X-ray crystal structure 221 – genetically encoded 61 Aurora kinase inhibitor 118ff., 175, 195ff., biphenyl amide (BPA) 124 242ff. BIRB-796 15ff, 49, 89, 101, 118ff., 148ff., 166, – clinical trial 248 245, 277ff. – in vitro phenotype 197 BMS354825 118 – screening 244 BMS387032/SNS032 127 – structure-guided design 244 BMS536924 120 – treatment for cancer 195ff. BMS582949 124 AV951 116 BMS599626 120 AX14585 356 Bosutinib (SKI606) 123 AX20017 356 BRET (bioluminescence resonance energy Axitinib (AG013736) 116 transfer) technology 58 AZD0530 123 BRK 99 AZD1152 202ff., 219, 249 Btk 77 AZD2171 116 Bub1 99 AZD6244 126 bump-and-hole approach 70 b c back pocket 146ff. Caco-2 cell 32ff. back-to-back design strategy 155, 169 CAL101 130 back-to-front design strategy 155, 166 CaMKII 99 BAY43-9006 89, 245 cancer Bcr-Abl (breakpoint cluster region–Abelson – treatment with Aurora kinase murine leukemia viral oncogene inhibitor 195ff. homologue) 54, 60, 80. 118 Canertinib 275 – inhibitor 91ff. Captopryl 90 – kinase 92 CARDIAK 99 – tyrosine kinase inhibitor 89, 118 casein kinase 2 (CK2) 133 BCRP (ABCG2) 36, 119 catalytic site inhibitor 234 5-benzimidazol-1-yl-3-aryloxy-thiophene-2- CD117 121 carboxamides 256 – inhibitor 121 benzothiophene 166 CD135 116 benzthiazole PLK1 inhibitor 254 CDC25c 250 BEZ235 129 Cediranib (AZD2171) 116, 121 BGT226 129 cell cycle BI1489 245 – oncology 231 BI2536 256f. cell line 1H,10H-[2,30] biindolylidene-3,20-dione 3- – genetically engineered 60 oxime 326 cell permeability 52 binding affinity 15 cellular kinase assay 45ff. bioactive conformation 92 – drug discovery application 46 biochemical kinase assay 4 – measurement of activity 55 – dependence on the kinase concentration 12 cellular kinase concentration 53 – identification of substrate 4 cellular kinase inhibition 53 – linearity between signal and kinase cellular protein kinase 305 concentration 4 – antiviral target 305ff. – optimization of reaction buffer 6ff. CEP701 116, 130 Index j367 CGP57148B 94 – small-molecule inhibitor 233ff. CGP79787/CGP79787D 116 cyclin-dependent kinase inhibitor chemical genetics 71 (PCI) 305ff., 323ff. Chemical Validation Library (CVL) 99 – combination therapy 336 Cheng–Prusoff equation 10, 48 – herpes virus 330 CHIR258/TKI258 116ff. – HIV 332ff. CHIR-265 172 – property 310f. 2-(2-chloro-phenyl)-5,7-dihydroxy-8-(3- – specificity 312ff. hydroxy-1-methyl-piperidin-4-yl)-chromen- – viral pathogenesis 337 4-one 326 cytochrome P450 enzyme (CYP450) 27ff., chronic myeloid leukemia (CML) 115 283 CI1033 118, 339 – isoform 35 CI1040 49, 125f. – measuring inhibition 39 CL-387785 51 cytokine suppressive anti-inflammatory drug Cla4 75 (CSAID) 275 combination therapy cytokine suppressive anti-inflammatory drug – PCI 336 binding protein (CSPB), see p38 MAP kinase comparative molecular field analysis (CoMFA) 93 d comparative molecular moment analysis dasatinib (BMS354825) 118, 145ff. (CoMMA) 93 deep pocket (DP) 17, 146ff. comparative molecular similarity analysis – design principle 145ff. (CoMSIA) 93 deep pocket binder 148 competition deep pocket binding inhibitor 25 – ATP 47 DELFIA (dissociation enhanced lanthanide conivaptan 125 fluorescent immunoassay) method 57 CP547632 116 design strategy CP690550 130 – comparative analysis 180 CP724714 120 DFG (Asp-Phe-Gly) motif 150 CSK 99 – DFG-in conformation 79, 153 CVT-313 327 – DFG-out conformation 17ff., 79, 153 CYC116 116, 250 N,N0-diarylurea-based inhibitor 286 CYC202 127 dibenzo[a,d]cyclohepten-5-ones 295 Cyclacel 127 6,11-dihydro-dibenzo-[b,e]oxepin-11-ones cyclin groove inhibitor (CGI) 240 – phenylamino-substituted 295 cyclin-dependent kinase (CDK) 127, 233f., dihydropyrimidopyrimidinone 160 310f. Dilmapimod 295ff. – CDK1 310ff., 330f. Dilmapimod tosylate 299 – CDK2 71, 92, 236ff., 310ff., 330ff. DiscoveRXs enzyme fragment – CDK3 311ff. complementation technology 59 – CDK4 236ff., 310ff. distribution coefficient 30 – CDK5 236, 310ff., 330f. Doramapimod 124 – CDK6 151, 236, 310ff. drug absorption – CDK7 236, 310ff., 330f. – experimental approach 30 – CDK8 310ff., 331 drug design – CDK9 133, 310ff., 331ff. – kinase inhibitor for signal transduction – CDK10 310ff. therapy 87ff. – CDK11 310ff. – rational, see rational drug design – CDK12 310ff. drug discovery – CDK13 310 – implication 25 – family 48 drug discovery application – inhibiting 239 – cellular kinase assay 46 – inhibition of CDK–cyclin association 242 drug metabolism 34 – property 310f. – experimental approach 34 368j Index – phase I and II processes 34 gatekeeper residue 74, 91 drug target 350 gefitinib (IressaTM) 91ff., 145ff. – validation by genetic inactivation 351 GK00687 168 Ò Ò Gleevec (Glivec , imatinib) 15, 49, 74ff., e 89ff., 118ff., 145f., 245, 338f. Ef-TU 78 Go6976 305 EGFR (epidermal growth factor receptor) 18, GSK690693 129 73ff., 89, 118 GSK1059615 130 – inhibitor 91 GSK1120212 125 EGFR/HER2 kinase inhibitor 119 GSK1363089(XL880) 116 EKB569 118 GW400426 77 electrochemiluminescent label 57 GW572016 18f. ELISA (enzyme-linked immunosorbent assay) GW-681323 299 method 56 GW-856553X 295 enzastaurin 126 enzyme h – chemically knock out 70 H7 355 enzyme donor (ED) peptide fragment 79 H-89 15 enzyme fragment complementation (EFC) Hck 179 technology 79 hepatic clearance 37 EO1606 294 hepatocyte growth factor (HGF) 122 EphB4 (ephrin receptor) 99 HER2 kinase 73, 120 epidermal growth factor receptor, see EGFR HER2 tyrosine kinase inhibitor 54 Epstein–Barr virus (EBV) 327ff. herpes simplex virus equilibrium ionization coefficient 31 – type 1 (HSV-1) 327ff. ERK1 kinase 51ff., 124 – type 2 (HSV-2) 327 ERK2 kinase 51ff., 124 herpes virus erlotinib (TarcevaTM) 18, 91, 145ff., 164 – antiviral activity 327 extended pharmacophore modeling 99 – PCI 330 Extended Validation Library (EVL) 99 hesperadin 197, 245ff. extracellular enveloped virion (EEV) 339 high-content analysis (HCA) 59 high-content screening 59 f HIV 327ff. FGFR (fibroblast growth factor receptor) 92, – PCI 332ff. 120 HIVAN (HIV-associated nephropathy) 337 flavopiridol 97, 127, 326ff. HKI-272 51, 119 FlexX program 90 HOG1 77 Flt (FMS-like tyrosine kinase) human cytomegalovirus (HCMV) 305, 327ff. – Flt-1 177 human T-lymphotropic virus-1 (HTLV-1) 327 – Flt3 60, 116, 151 hybrid design strategy 155ff., 173 – Flt-4 177 hydrogen bond acceptor (HBA) 180 fluorescent labels in kinases (FLiK) 79 hydrogen bond donor (HBD) 180 fluorescent probe 21 hydrophobic back pocket 104 Fms/CSFR 151 7-hydroxy-staurosporine
Recommended publications
  • Signal Transduction Guide

    Signal Transduction Guide

    Signal Transduction Product Guide | 2007 NEW! Selective T-type Ca2+ channel blockers, NNC 55-0396 and Mibefradil ZM 447439 – Novel Aurora Kinase Inhibitor NEW! Antibodies for Cancer Research EGFR-Kinase Selective Inhibitors – BIBX 1382 and BIBU 1361 DRIVING RESEARCH FURTHER Calcium Signaling Agents ...................................2 G Protein Reagents ...........................................12 Cell Cycle and Apoptosis Reagents .....................3 Ion Channel Modulators ...................................13 Cyclic Nucleotide Related Tools ...........................7 Lipid Signaling Agents ......................................17 Cytokine Signaling Agents ..................................9 Nitric Oxide Tools .............................................19 Enzyme Inhibitors/Substrates/Activators ..............9 Protein Kinase Reagents....................................22 Glycobiology Agents .........................................12 Protein Phosphatase Reagents ..........................33 Neurochemicals | Signal Transduction Agents | Peptides | Biochemicals Signal Transduction Product Guide Calcium Signaling Agents ......................................................................................................................2 Calcium Binding Protein Modulators ...................................................................................................2 Calcium ATPase Modulators .................................................................................................................2 Calcium Sensitive Protease
  • Identification of Candidate Repurposable Drugs to Combat COVID-19 Using a Signature-Based Approach

    Identification of Candidate Repurposable Drugs to Combat COVID-19 Using a Signature-Based Approach

    www.nature.com/scientificreports OPEN Identifcation of candidate repurposable drugs to combat COVID‑19 using a signature‑based approach Sinead M. O’Donovan1,10, Ali Imami1,10, Hunter Eby1, Nicholas D. Henkel1, Justin Fortune Creeden1, Sophie Asah1, Xiaolu Zhang1, Xiaojun Wu1, Rawan Alnafsah1, R. Travis Taylor2, James Reigle3,4, Alexander Thorman6, Behrouz Shamsaei4, Jarek Meller4,5,6,7,8 & Robert E. McCullumsmith1,9* The COVID‑19 pandemic caused by the novel SARS‑CoV‑2 is more contagious than other coronaviruses and has higher rates of mortality than infuenza. Identifcation of efective therapeutics is a crucial tool to treat those infected with SARS‑CoV‑2 and limit the spread of this novel disease globally. We deployed a bioinformatics workfow to identify candidate drugs for the treatment of COVID‑19. Using an “omics” repository, the Library of Integrated Network‑Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID‑19 drugs and publicly available SARS‑CoV‑2 infected cell lines to identify novel therapeutics. We identifed a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID‑19, the remaining 12 have antiviral properties and 6 have antiviral efcacy against coronaviruses specifcally, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug fndings are discordant with (i.e., reverse) SARS‑CoV‑2 transcriptome signatures generated in vitro, and a subset are also identifed in transcriptome signatures generated from COVID‑19 patient samples, like the MEK inhibitor selumetinib. Overall, our fndings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID‑19 and identify promising novel targets that are worthy of further investigation.
  • Tanibirumab (CUI C3490677) Add to Cart

    Tanibirumab (CUI C3490677) Add to Cart

    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
  • Protein Kinase Inhibitors

    Protein Kinase Inhibitors

    Protein Kinase Inhibitors Protein kinases are key regulators in cell signaling pathways in eukaryotes. They act by chemically modifying other proteins with phosphate groups, a process called phosphorylation. These enzymes are known to regulate the majority of cellular pathways, especially those involved in signal transduction. The human genome codes for more than 500 protein kinases. Misregulation of these proteins has been linked to several diseases, including cancer, psoriasis and chronic inflammation. For this reason, small molecule protein kinase inhibitors have become important research tools for the elucidation of the varied roles of kinases and their mechanisms of action. These molecules have been key developments in drug pipelines of the pharmaceutical and biotechnology industries and also in the growing need to treat cancer and inflammation. Item Description Application Sizes J63983 Wortmannin, Penicillium A specific and irreversible inhibitor of phosphatidyl inositol 10mg, 25mg, 50mg funiculosum, 99+% 3-kinase (IC 2-5nM) 50 J63525 Fasudil, 98+% A potent rho-kinase inhibitor with antivasospastic properties 10mg, 50mg J60594 Fasudil dihydrochloride, A potent rho-kinase inhibitor with antivasospastic properties 250mg, 500mg, 1g 99+% J60751 Fasudil monohydrochloride A potent rho-kinase inhibitor with antivasospastic properties 100mg, 200mg, 1g 99+% J60308 Tyrphostin A23, 99% An inhibitor of EGF receptor kinase with an IC50 value of 35 5mg, 10mg, 25mg µM in the human epidermoid carcinoma cell line A431 J63090 K252c Inhibits protein kinase c with IC50 of 214 nM. Inhibits CaM 1mg, 5mg kinase with IC50 of 297 µM for the brain enzyme. J61687 Protein Kinase inhibitor Also called K252a. An alkaloid isolated from Nocardiopisis sp. 1mg, 5mg, 25mg soil fungi.
  • Access to Cancer Medicines in Australia

    Access to Cancer Medicines in Australia

    Access to cancer medicines in Australia Medicines Australia Oncology Industry Taskforce July 2013 Contents Glossary ..................................................................................................................................... i Executive summary .................................................................................................................... i 1 Background ..................................................................................................................... 1 1.1 Purpose of this report ....................................................................................................... 2 1.2 Methods ........................................................................................................................... 3 1.3 Report structure ............................................................................................................... 9 2 Cancer in Australia and other countries ......................................................................... 10 2.1 Population statistics on cancer ........................................................................................ 10 2.2 Population impacts of cancer in Australia ........................................................................ 24 2.3 Summary ........................................................................................................................ 33 3 Current and future cancer medicines ............................................................................ 34 3.1 Current
  • Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in Vitro and in Vivo

    Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in Vitro and in Vivo

    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Genetik Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in vitro and in vivo - Towards Response Prediction in Cancer Therapy with Kinase Inhibitors Michaela Bairlein Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ. -Prof. Dr. K. Schneitz Prüfer der Dissertation: 1. Univ.-Prof. Dr. A. Gierl 2. Hon.-Prof. Dr. h.c. A. Ullrich (Eberhard-Karls-Universität Tübingen) 3. Univ.-Prof. A. Schnieke, Ph.D. Die Dissertation wurde am 07.01.2010 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 19.04.2010 angenommen. FOR MY PARENTS 1 Contents 2 Summary ................................................................................................................................................................... 5 3 Zusammenfassung .................................................................................................................................................... 6 4 Introduction .............................................................................................................................................................. 8 4.1 Cancer ..............................................................................................................................................................
  • 1477-1502 Page 1477 Vijay

    1477-1502 Page 1477 Vijay

    Vijay. K * et al. /International Journal Of Pharmacy&Technology ISSN: 0975-766X CODEN: IJPTFI Available Online through Review Article www.ijptonline.com PROTEIN KINASES: TARGETS FOR DRUG DISCOVERY Sri Harika. K, Rama lakshmi. K, Vijay. K* University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur. Email:[email protected] Received on 25-08-2011 Accepted on 14-09-2011 Abstract Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase’s substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways results in the reprogramming of gene expression through the direct regulation of transcription factors or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy, ischemia/reperfusion injury, angiogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Key words: protein kinase, signaling pathway, cell function. Introduction: Targets: Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on.
  • Kinase-Targeted Cancer Therapies: Progress, Challenges and Future Directions Khushwant S

    Kinase-Targeted Cancer Therapies: Progress, Challenges and Future Directions Khushwant S

    Bhullar et al. Molecular Cancer (2018) 17:48 https://doi.org/10.1186/s12943-018-0804-2 REVIEW Open Access Kinase-targeted cancer therapies: progress, challenges and future directions Khushwant S. Bhullar1, Naiara Orrego Lagarón2, Eileen M. McGowan3, Indu Parmar4, Amitabh Jha5, Basil P. Hubbard1 and H. P. Vasantha Rupasinghe6,7* Abstract The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein- coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies. Keywords: Kinases, Kinase inhibition, Small-molecule drugs, Cancer, Oncology Background Recent advances in our understanding of the fundamen- Kinases are enzymes that transfer a phosphate group to a tal molecular mechanisms underlying cancer cell signaling protein while phosphatases remove a phosphate group have elucidated a crucial role for kinases in the carcino- from protein.
  • Protein Kinase C: a Target for Anticancer Drugs?

    Protein Kinase C: a Target for Anticancer Drugs?

    Endocrine-Related Cancer (2003) 10 389–396 REVIEW Protein kinase C: a target for anticancer drugs? HJ Mackay and CJ Twelves Department of Medical Oncology, Cancer Research UK Beatson Laboratories, Alexander Stone Building, Switchback Road, Glasgow G61 1BD, UK (Requests for offprints should be addressed to C Twelves; Email: [email protected]) (HJ Mackayis now at Department of Drug Development, Medical Oncology,Princess Margaret Hospital, Toronto, Ontario, Canada) (CJ Twelves is now at Tom Connors Cancer Research Centre, Universityof Bradford, Bradford, UK) Abstract Protein kinase C (PKC) is a familyof serine/threonine kinases that is involved in the transduction of signals for cell proliferation and differentiation. The important role of PKC in processes relevant to neoplastic transformation, carcinogenesis and tumour cell invasion renders it a potentiallysuitable target for anticancer therapy. Furthermore, there is accumulating evidence that selective targeting of PKC mayimprove the therapeutic efficacyof established neoplastic agents and sensitise cells to ionising radiation. This article reviews the rationale for targeting PKC, focuses on its role in breast cancer and reviews the preclinical and clinical data available for the efficacyof PKC inhibition. Endocrine-Related Cancer (2003) 10 389–396 Introduction anchoring proteins (Csuki & Mochley-Rosen 1999, Way et al. 2000). The protein kinase C (PKC) family consists of at least 12 The phospholipid diacylglycerol (DAG) plays a central isozymes that have distinct and in some cases opposing roles role in the activation of PKC by causing an increase in the in cell growth and differentiation (Blobe et al. 1994, Ron & affinity of PKCs for cell membranes which is accompanied Kazanietz 1999).
  • Role of Vegfs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models

    Role of Vegfs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models

    International Journal of Molecular Sciences Review Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models 1 1 2, 1, , Claudia Ceci , Maria Grazia Atzori , Pedro Miguel Lacal y and Grazia Graziani * y 1 Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; [email protected] (C.C.); [email protected] (M.G.A.) 2 Laboratory of Molecular Oncology, “Istituto Dermopatico dell’Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico”, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; [email protected] * Correspondence: [email protected]; Tel.: +30-0672596338 Equally contributing co-last authors. y Received: 21 January 2020; Accepted: 14 February 2020; Published: 18 February 2020 Abstract: The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process.
  • Online Appendix

    Online Appendix

    The More We Die, The More We Sell? A Simple Test of the Home-Market Effect Online Appendix Arnaud Costinot Dave Donaldson MIT, CEPR, and NBER MIT, CEPR, and NBER Margaret Kyle Heidi Williams Mines ParisTech and CEPR MIT and NBER December 28, 2018 1 Contents A Theoretical Appendix3 A.1 Multinational Enterprises (Section III.1)..........................3 A.2 Log-Linearization (Section III.2)...............................3 A.3 Beyond Perfect Competition (Section III.3).........................6 A.3.1 Monopolistic Competition..............................6 A.3.2 Variable Markups...................................7 A.3.3 Endogenous Innovation...............................8 A.3.4 Price Regulations...................................9 A.4 Bilateral Sales (Section VI.1)................................. 12 B Empirical Appendix 12 B.1 Rich versus Poor Countries................................. 12 B.2 Additional Empirical Results................................ 13 B.3 Benchmarking IMS MIDAS data.............................. 13 B.3.1 Benchmarking to the OECD HealthStat Data................... 13 B.3.2 Benchmarking to the MEPS Data.......................... 14 B.4 ATC to GBD Mapping.................................... 15 2 A Theoretical Appendix A.1 Multinational Enterprises (Section III.1) In this appendix, we illustrate how to incorporate multinational production into our basic envi- ronment. Following Ramondo and Rodríguez-Clare(2013), suppose that each firm headquartered in country i that sells drugs targeting disease n in country j 6= i can choose the country l in which its production takes place. If l = i, then the firm exports, if l = j, it engages in horizontal FDI, and if l 6= i, j, it engages in platform FDI. Like in Ramondo and Rodríguez-Clare(2013), we assume that firm-level production functions exhibit constant returns to scale, but we further allow for external economies of scale at the level of the headquarter country for each disease.
  • ©Ferrata Storti Foundation

    ©Ferrata Storti Foundation

    ORIGINAL ARTICLES Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT Karoline V. Gleixner, Matthias Mayerhofer, Karoline Sonneck, Alexander Gruze, Puchit Samorapoompichit, Christian Baumgartner, Francis Y. Lee, Karl J. Aichberger, Paul W. Manley, Doriano Fabbro, Winfried F. Pickl, Christian Sillaber, Peter Valent ABSTRACT From the Department of Internal Background and Objectives Medicine I, Division of Hematology & Hemostaseology (KVG, KS, CB, In a majority of all patients with systemic mastocytosis (SM) including those with KJA, CS, PV); Institute of Immunology mast cell leukemia (MCL), neoplastic mast cells (MC) display the D816V-mutated vari- (AG, WFP), Clinical Institute of ant of KIT. The respective oncoprotein, KIT D816V, exhibits constitutive tyrosine Medical and Chemical Laboratory kinase (TK) activity and has been implicated in malignant cell growth. Therefore, sev- Diagnostics (MM); Center of Anatomy eral attempts have been made to identify KIT D816V-targeting drugs. and Cell Biology, Medical University of Vienna, Austria (PS); Oncology Design and Methods Drug Discovery, Bristol-Myers Squibb, We examined the effects of the novel TK-inhibitor dasatinib alone and in combination Princeton, NJ, USA (FYL); Novartis Pharma AG, Basel, Switzerland with other targeted drugs on growth of neoplastic MC. (PWM, DF). Results Funding: this study was supported by Confirming previous studies, dasatinib was found to inhibit the TK activity of wild type the Fonds zur Förderung der (wt) KIT and KIT-D816V as well as growth and survival of neoplastic MC and of the Wissenschaftlichen Forschung in MCL cell line, HMC-1. The growth-inhibitory effects of dasatinib in HMC-1 cells were Österreich (FWF) grant #P-17205- found to be associated with a decrease in expression of CD2 and CD63.