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

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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 – 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 305ff. active analogue approach (AAA) 92 ARQ197 123 acute myelogenous (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 – 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, – 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 (SKI606) 123 AX20017 356 BRET (bioluminescence resonance energy (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 – 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 (AZD2171) 116, 121 BGT226 129 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 (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. DiscoveRX’s 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 , ) 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 () 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 (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- 127 c-Fos 60 (R935788) 130 i FR167653 278 IC50 13 FRET biosensor 61 IGF1 receptor (IGF1R) 120 front-to-back design strategy 155ff. IGFR insulin-like growth factor receptor 120 furopyrimidine 160 IkB 51 IkB kinase (IKK) 131 Ò g imatinib (Gleevec ) 15, 49, 74ff., 89ff., 118ff., GAK 99 145f., 245, 338f. gastrointestinal stromal tumor (GIST) 118 impedance measurement 62 Index j369

INCB018424 130 – personalized therapy 96 indirubin-30-monoxime 326ff. – screening 45ff. 305 – second-generation 105 inner centrosome protein (INCENP) 221, – signal transduction therapy 87ff., 115ff. 243ff. – small-molecule, see small-molecule kinase infection 132 inhibitor inflammation 131 – tool 69ff. – kinase inhibitor 131 – unusual 15 inhibitor kinase signaling – effect 54 – compartmentalization 55 – preincubation 22 kinase signaling cascade inositol polyphosphate 5-phosphatase – ultrasensitivity 51 (SHIP2) 51 kinase substrate insulin receptor (IR) 120 – identification 76 insulin receptor kinase (IRK) 151 KinaTorTM technology 97ff. investigational new drug (IND) 99 c-Kit 80, 118, 121, 151 ionization c-Kit receptor 121 – measurement 30 KIT 121 IressaTM 18, 91, 145f. KIT/FLT3 inhibitor 118 1-(5-isoquinolinesulfonyl)-2- KP3721 117 methylpiperazine 355 KRN383 117 j l JAK () 130 L-167782 280 – JAK2 kinase 116 L-786134 280 JC virus 327 label-free assay 62 JNK (c-Jun N-terminal kinase, MAPK8) 126, (TykerbTM) 15ff., 89ff., 145ff., 169ff. 131, 271ff. large T antigen (T Ag) protein 335f. – Jnk2 99 lck (lymphocyte-specific kinase) 92, 151, 175ff. k LeapFrog 90 Kaposi’s sarcoma herpesvirus (KSHV) 327ff. (CEP701) 116, 130 KDR 151, 163ff., 178 ligand efficiency (LE) 180ff. Ki23057 121 ligand-based drug design 92 kinase Lipinski’s rule of five 28 – analogue-sensitive 69ff. lipophilicity 31 – specifically targeting 78 – measurement 30 – untouchable 108 liver clearance 37 kinase activity losmapimod (8565533) 124, 295 – detergent 9 luminex technology 57ff. – ion 9 LY294002 51, 73, 254ff. – MgCl2 and MnCl2 concentration 9 LY317615/enzastaurin 126 – phosphatase inhibitor 9 LY333531/Ruboxistaurin 126 kinase family selectivity Lyn 99 – analysis 62 kinase family-biased master key concept 105 m kinase inhibition 76 Madin-Darby canine kidney cell (MDCK) 32 kinase inhibitor magic methyl 154ff. – affinity chromatography 97 MAPK (mitogen-activated protein – cellular efficacy 47 kinase) 131 – dissection of signaling pathway 46 – pathway 60, 121 – immobilized 63 maribavir 305 – infectious disease 131 master key concept 102 – inflammation 131 Master Library (ML) 99 370j Index

MEK 273 NM-PP1 73ff. – MEK1 77 non-ATP binding site-directed kinase – MEK2 51 inhibitor 101 Met (mesenchymal-epithelial transition non-ATP competitive inhibitor 148 factor) 99, 122 NPM-Alk 60 metabolic stability NPV-AEW541 120 – measurement 37 NPV-AFG210 169 5-methylisoxazole flavopiridol derivative number of rotatable bond (NROT) 180 333 NVP-AEG082 177 N-methylpiperidinyl-imidazole 283 4-(4-methyl-piperazin-1-ylmethyl)-N-[4- o methyl-3-(4-pyridin-3-ylpyrimidin-2- olomoucine 327 ylamino)-phenyl]-benzamide 338 ON 01910.Na 257 mHOG1, see p38 MAP kinase ON012380 50 Michaelis–Menten constant 10 oncology Michaelis–Menten equation 13 – cell cycle 231 /PKC412 126 OPC-67683 350 355 orthogonal ligand 71 mixed lineage kinase (MLK) 274 orthogonal receptor pair 71 MK-0457 (VX-680) 118ff., 198, 214ff., OSI-774 18 249 oxalylamino-methylene-thiophene MK5108 128, 249 sulfonamide (OMTS) 357 ML3163 278 MLN8054 202, 219, 250 p MLN8237 128 P-glycoprotein (P-gp, MDR1, ABCB1) 27ff. morin 254 p21-activated kinase (PAK) Cla4 75 Motesanib (AMG706) 121 p38 MAP kinase (p38 MAPK, CSPB, mHOG1, MPAQ 160ff. SAPK2) 21, 49, 92ff., 123ff., 271ff. MRP2 (ABCC2) 36 – first-generation inhibitor 278 Msk kinase 73 – inhibitor 89, 101, 118, 275 mTOR 48 – medicinal chemistry approach for the multiple target kinase inhibitor 102 inhibition 271ff. multiplexing 57ff. p38a MAP kinase (MAPK14) 20, 49, 151ff., multitargeted drug 97 167ff., 271ff., 287ff. Mycobacterium 349ff. – inhibitor 124, 164ff. – phosphosignaling networks 349ff. p38b MAP kinase 272 Mycobacterium tuberculosis STPK 351 – inhibitor 293f. – inhibitor 355 p38c MAP kinase 281 MyD88 (myeloid differentiation 88) 131 p38d MAP kinase 281 P276-00 127 n P1446A-05 127 NA-PP1 73ff. PA-824 350 naphthoylamide 169 Pamapimod 300 NCI-H460 256 pan-kinase inhibitor 99 NCT00090987 338 pan-tyrosine kinase inhibitor 97 (HKI272) 119 parallel artificial membrane assay Nested Chemical LibraryTM (NCL) (PAMPA) 32 technology 99 partition coefficient (P) 30 3DNET4WTM software 99 passive diffusion 28 NexavarTM 145ff. PCI, see cyclin-dependent kinase inhibitor NF-kB 51, 131f. PD089828 125 NGIC-I 305 PD166866 125 (AMN107, TasignaTM) 118ff., 145ff., PD168393 73 169 PD173074 121 Index j371

PD173955 236 – cellular 305 PD180970 97 protein kinase inhibitor PD0183812 237 – anticancer drug development 231 PD184352 125 – antiviral activity 338 PD0325901 126 – classification 148 PD0332991 127, 238f. – design 231ff. PDGF family – design principles for targeting 145ff. 168 – discovery 231ff. permeability protein phosphatase – measurement 31 – drug target 350 personalized therapy protein tyrosine phosphatase (PTP) – kinase inhibitor 96 350ff. PG-1009247 180 PS540446 124 Ph797804 124 PTEN 51 PHA665752 123 PTK787 116 PHA-680626 245ff. pure peptide binding site inhibitor 101 PHA-680632 198, 215ff., 245ff. purpurogallin 259 PHA-739358 128, 198, 215ff. purvalanol 332 pharmacodynamic (PD) parameter 26 purvalanol A 252 Phe pocket 146 PX866 129 phenylaminopyrimidine (PAP) 160 pyrazole acetanilide inhibitor 212 phospho-p38 60 pyrazolo acetanilide quinazolines 208 phosphohistone 60 pyrazolopyrimidines 179 phosphorylation network 69ff. pyridinyl-imidazole inhibitor 278 PI3K (phosphoinositide 3-kinase) 129ff. pyridodiazines 160 – inhibitor 73, 252 pyridotriazine 160 PI3K/Akt 133 pyridylether 160 PI3 kinase/Akt/mTOR pathway 60 pyrimidinoquinazoline 205ff. piperidin-4-yl-imidazoles 283 pyrrolopyrimidine 179 PKA (cAMP-activated/dependent protein kinase) 58, 71, 92, 233 q PKB (protein kinase B) 129 quantitative structure–activity relationship PKC (protein kinase C) 126 (QSAR) model 92f. – inhibitor 160 – 3D 92 PKC412 126 – prediction-oriented 99f. PKI166 120 quercetin 254 PknG 133 platelet-derived growth factor receptor r (PDGFR) 118ff. R112 130 – a (PDGFRa)80 R763 250 PLK 250 R788/fostamatinib (R935788) 130 polar surface area (PSA) 180 R1487 299 polo-box domain (PBD) 251ff. Rad51 77 polo-like kinase (PLK) 250 Rad54 77 – inhibitor 250ff. B-Raf kinase 151, 168 – PLK1 250f. C-Raf 168 – small-molecule inhibitor 252ff. RAF-265 172 Poloxin 259 RANTES 336 poloxipan 259 rapamycin 50 PP2 54 rational drug design protein function – concept 88 – switch off 69 – kinase inhibitor for signal transduction protein kinase therapy 87ff. – antiviral target 305ff. RDEA119 125 372j Index

receptor tyrosine kinase (RTK) 145 – pharmacokinetic (PK) behaviour 3 receptor–ligand complex 17 solubility 31 Red1 77 – measurement 30 reporter displacement assay 22 (NexavarTM) 15, 49, 115ff., residence time 15 145ff., 166 X receptor (RXR) 78 SP006125 355 retrodesign approach 159 SP600125 126 ribofuranosyl benzimidazole 305 SprycelTM 118, 145f. ribose binding pocket 104 SR144528 125 RIP2 kinase (RICK, RIPK2, RIP2) 54, 99 Src 72, 123 RO3201195 288ff. – kinase 92 Ro5126766 125 staurosporine 252 Rock II 6ff. STI-571 55, 94, 236ff. roscovitine 325ff. stress-activated protein kinase 2 (SAPK2), R-roscovitine 127 see p38 MAP kinase Rsk1, Rsk2 73 structure-based drug design (SBDD) 89 Ruboxistaurin 126 – 3D 89 rule of five 28 SU5402 121 RWJ67657 283f. SU5416 116 SU6668 116 s SU11248 115ff. SB1518 130 SU11271 123 SB202190 123 SU11274 123 SB203580 49ff., 94, 123, 163, 272ff. substrate activity screening (SAS) SB210313 282 357f. SB235699 282f. substrate phosphorylation 54 SB242235 123, 283ff. – level 51 SB610677 295 (SU11248, SutentTM) 115ff., SB681323 123, 295ff. 145ff. SB856553 (GW-856553X) 295 surface plasmon resonance (SPR) 19 SCIO323 124, 294 surface-exposed front area 104 SCIO469 124, 293 SX011 293 SD06 288 Syk (spleen tyrosine kinase) 130ff. selectivity pocket 146 127, 326 t Semaxinib (SU5416) 116 TAK715 124, 292 serine/threonine protein kinase Tandutinib 116 TM (STPK) 350ff. Tarceva (erlotinib) 18, 91, 145ff., 164 – drug target 350 target – fi – function 352 shing 97 – – mechanism 352 preincubation 22 – – substrate 352 selection 93 signal transduction therapy target family-biased master key concept – rational drug design of kinase 102 TM inhibitor 87ff. Tasigna 145f. SILAC (stable isotope labeling by amino TG100-115 129 acids) 62f. TG101348 130 SKF86002 278ff. Tie-2 (tunic internal endothelial cell receptor) SKI606 123 kinase 151, 163ff. small-molecule inhibitor TKI258 116ff. – cyclin-dependent kinase 233 TMC207 350 – structure-guided design 233 Tozasertib 249 small-molecule kinase inhibitor transporter assay – – in vitro characterization 3ff. P-gp interaction 33 Index j373 transporter protein 28 VX745 124, 294ff. triphosphate binding region 104 VX-745-like compound 297 tuberculosis (TB) therapeutics 349ff. TM Tykerb 145f. w type II inhibitor 79, 148ff. washout experiment 18 – design strategy 155 WHI-P97 130 – property 184f. WO00017175 294 tyrphostin 101 WO09958502 294 WO2004072038 294 u WO2006/134382A1 296 UCN01 (7-hydroxy-staurosporine) 127 wortmannin 53, 252 UDP glucuronosyl (UGT) 35ff. ultrasensitivity x – kinase signaling cascade 51 xenobiotics 36 uridine 50-diphosphoglucuronic acid XL019 130 (UDPGA) 35 XL147 130 XL184 123 v XL418 129 validation 93 XL518 125 116ff. XL765 130 varicella-zoster virus (VZV) 327ff. XL880 116 116, 177 VEGF (vascular endothelial growth y factor) 168 Y-27632 15 VEGFR (VEGF receptor) 92, 115, 172f. Yes 99 viral pathogenesis – PCI 337 z VX509 130 Zactima/ZD6474 116 VX680 (MK-0457) 118ff., 198, 214ff., 249 ZD-1839 18 VX689 (MK5108) 128, 249 ZK222584 116 VX702 124, 294 ZM447439 (ZM) 197ff., 249