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Protein Kinases As Drug Targets

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Protein Kinases As Drug Targets 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
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