Subject Index

Locators in bold refer to figures/

diagrams

Kinases and their inhibitors appearunder the same entry

A375 gene 146

A-769662 297

AarF domain containing kinases 31

Abbott inhibitors 168–9, 169, 170

ABC294640 199

ABC747080 199

ABI-009 186

ABL (Abelson leukemia) kinases. see

BCR-ABL kinase

ACK (acetate) kinases 31

activation, kinase 129–31, 296–7

acute diseases 5–6

lung injury 226

respiratory distress syndrome 226

ADCK (AarF domain containing)

kinases 31

additive effects 294. see also combi-

nation therapy

adenine guanine cytosine kinases 2,

221–2, 267

adenosine kinases 167–72, 169, 170,

171, 172, 202. see also AMPK

adenosine triphosphate. see ATP

ADME (absorption, distribution,

metabolism, excretion) 291

ADP production 14–15

ADZ8055 186, 191

Aerie Pharmaceuticals 222

afatinib 142, 143, 287, 288

AGC (adenine guanine cytosine)

kinases 2, 221–2, 267

age related macular degeneration 236

AKT (protein kinase B) kinases 24,

25, 31, 54, 55, 55–6, 56, 152,267, 293

algorithms

BREED 68

data analysis 22, 23

ALK (anaplastic lymphoma) kinases

31

alkynylpyrimidines 168, 169

allergies 193

allosteric

activators, glucokinase. see gluco-

kinase

modulators 293–4

sites, inhibitor selectivity 116

AMA37 191, 192

Ambit Biosciences 81, 108

algorithms 22, 23

assays 11–12, 15, 30–53

AMD (age related macular degen-

eration) 236

American College of Rheumatology

228, 235

amino acids 80, 263. see also indivi-

dual AAs by name

aminoethanol 199

AMPK (adenosine monophosphate-

activated protein) kinase 31–2,

296–7. see also adenosine

kinases

analgesic effects, p38 inhibitors 224

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anaplastic lymphoma kinases 31

angiogenesis 178

anilino-quinazolines 67, 119

AP-23846 137, 138

AP-23864 138

Apicomplexa taxon 265. see also

malaria

apo-protein structure 64

apoptosis 172, 199

approved inhibitors ix, 4, 5

Area Under the Curve (AUC) values

290

arginine 59, 60, 63, 134

ARMS (acute respiratory distress

syndrome) 226

ARQ 068 63, 63

ARQ 069 63, 63, 64, 64, 64

ARQ 197 61, 62, 62

ARQ 198 63

ARQ 523 63, 63

Arqule 61, 63

Array Biopharma 254

ARRY-142886 87, 88

ARRY-403 254

ARRY-588 254

ARRY-797 223, 224

Artemesinin 273

AS-252424 185, 186, 187

assays, commercial 8–16, 30–53

asthma 229

AstraZeneca 66, 68, 73, 90, 186, 191,

192, 227, 252, 293

ataxia telangiectasia mutated kinase

32, 189, 193

atherosclerosis 224, 226

ATP (adenosine triphosphate)

binding sites 98

dependence 104–5, 105, 106, 115,

115, 116, 120

intracellular effects 88–9

ATR (ataxia telangiectasia mutated)

kinases 32, 189, 193

Aurora kinases 137, 144–5

autimmune disease 229, 231

AVL292 287

AZD1656 252

AZD-6244 146

AZD6370 252

B534c 197

bacteriophages, T7 81

BAY 80-6946 181, 182

Bayer 181

BCR-ABL (breakpoint cluster

region) kinases 61, 126, 127,

132, 137, 188

chronic myeloid leukemia 132

inhibitors 293–4, 294. see also

imatinib; nilotinib

kinase activation 130

non-cancer applications 237–8

resistance mutations 133–5, 134,

144, 153

bevacizumab 176, 188

BEZ235 178, 181, 193

BGT226 178

BI 2536 25, 25, 26

Biacore biosensors 108

biarylbutyranilide inhibitors 102

BIBW-2992 142, 143, 287, 288

binding/binding assays

competition 81, 108

imatinib 126–7

protein kinase family 99, 100, 101,

97–103, 102, 107–9

BIRB-796 58, 59, 223

BKM120 178, 179

Bl-2536 145

BMS-582949 223, 224

BRAF kinases 33, 60, 61, 83, 86, 114,

127, 290

binding modes 100

inhibition mechanisms 103

mutations/drug resistance 146, 147,

148, 149

BRafV600E 290

breakpoint cluster region. see BCR-

ABL kinases

breast cancer 101

EGFR kinases 139, 150

304 Subject Index

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Her-2 inhibitors 127, 151

phosphatidylinositol-3-kinases175–9, 182, 189

pseudokinases 298

BREED algorithm 68

Bristol-Myers Squibb 90

BYL719 179

C797S gene 147

CAL-101 185, 187

Caliper Life Sciences, assay panels 11,

13–14, 30–53

Calistoga Pharmaceuticals 185

CAMK (calcium-calmodulin regu-

lated kinases) 33, 264, 269

cAMP-dependent protein kinase 97,

267

cancer 4, 8. see also specific cancers by

name

drug resistance. see mutations/drugresistance

imatinib 88

patient selection 119–20

sugar kinases 162–3, 163

canertinib 142, 142

carboplatin 176

cardiovascular disease 4, 164, 221,

226

Carna kinome assay 14, 30–53

casein kinases 35, 264, 269

catalysis inhibition mechanisms 103

catalytic assays 12–13

CBL-1309 187

CC-223 188

CDK. see cyclin dependent protein

kinases

cell permeability 89, 90

cell signaling. see signaling pathways

Cell Signaling Technology website 2

cellular assays 88–9. see also in vitro

to in vivo translation

Cellzome 15, 16

ceramide kinase (CERK) 196, 196–7

cerebral infarction 221

cerebral vasospasm 218

Cerylid 182

checkpoint kinase-1 (CHK1) inhibi-

tors 73, 74

C-helix 97, 101, 103, 114, 140, 142

chemical connectivity, kinome 16–21,

17, 19, 21, 26

Cheng-Prusoff relationship 105, 112

choline kinase (CHK) 35, 103, 161,195

chronic diseases 5–6, 7–8

leukemia 100, 117, 126–7, 132, 133,

187, 219, 295

myeloproliferative disorders 132

obstructive pulmonary disease 225,

226, 227

cis-platinum 202

CK (casein kinases) 35, 264, 269

c-Kit (type III transmembrane recep-tor) kinases 89, 89. see also

KIT kinase

gastrointestinal stromal tumors

132, 295

inhibitors 237–8. see also pazopa-

nib

mutations/drug resistance 132, 153

receptors 236

Cl-1033 118, 147

Cl-1040 146

classification, protein kinases 1, 2

cMET kinases 61, 62, 62, 63, 116. see

also MET kinase

CMGC (cyclin-dependent, Mitogen-

activated, Glycogen synthase

and CDK-like) kinases 2, 269

colorectal cancer 150

combination therapy 117, 292–5

commercial assays 8–16, 30–53

compensatory inflammatory path-

ways 223

competition binding assays 81, 108

COT (serine/threonine) kinase 149

covalent inhibition, protein kinase

family 114, 118–19

CP466722 192, 193

CP-690 550 6, 231–2, 233–4

Subject Index 305

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CRAF kinases 60, 61, 127

C-reactive protein 223, 225

Crohn’s disease 58, 234

cross-reactivity 81

cross-screen (X-screen) 8, 9, 10

crystaline structures. see structure; X-

ray crystallography

cyano-quinazolines 67

cyclin-dependant kinases 34–5, 68, 69,

83, 86

kinase activation 131

methyl group 90

Plasmodium spp. 269

cyclin-dependent, Mitogen-activated,

Glycogen synthase and CDK-

like (CMGC) kinases 2, 269

Cys67 26

Cys797 119

cysteine residues 70, 71, 142

cytidine analogs 165

cytokines, inflammatory 222, 229–30,

230–2, 234

D816H gene 136

D816V gene 136

D820G gene 136

danusertib 137, 138

Darwin Pharma 202

dasatinib ix, 5, 81, 82, 83, 85, 127,

128, 134

BCR-Abl inhibition 137

inhibitor selectivity 116

mutations/drug resistance 132–3,

135, 147

optimization of target modulation

291

data analysis profiling 22, 23

DCC-2036 61, 61

Deciphera pharmaceuticals 58, 59, 61

DCK (deoxycitidine) kinase 166, 166–

7, 167

del1747-752 mutation 143

del-19 mutations 139

delayed type hypersensitivity model235

dendrogram-based interaction map

81

dental pain 7

deoxycitidine kinase 166, 166–7, 167

depression, p38a inhibitors 226

dermatofibroma sarcoma protuber-

ans 117, 132

DFG (aspartic acid-phenylalanine-

glycine) motif 57, 59, 61–3, 71,

72, 85. see also BRAF kinases;

P38 kinases

binding modes 99

inhibition mechanisms 103

medicinal chemistry perspective 81,82

mutations/drug resistance 130, 130,

134

slow binding/tight binding/covalent

inhibition 114

diabetes 164. see also glucokinase,

allosteric activators

diacylglycerol kinase (DGK) 195

dilmapimod 226

Disease Activity Scores (DAS) 224

DMARD 224, 232

DNA-PK 189

DP-1376 60, 61

DP-802 59, 60, 60, 61

Drugs for Neglected Disease

Initiative 262

drug resistance. see mutations/drugresistance

dry eye disease 234

E255K resistance 133, 134, 147

EGFR (epidermal growth factor

receptor) 37, 57, 82, 83, 85, 87,

92, 114, 115, 118, 127. see also

erlotinib; gefitinib

binding modes 101

breast cancer 150, 153

inhibitor selectivity 116, 117

irreversible inhibitors 287

kinase activation 131

306 Subject Index

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mutations/drug resistance 119,

139–44, 140, 142, 143, 144, 146, 151

resistance mechanisms not invol-

ving kinase 147, 148

EGFR T790M 288, 289

EKI-785 143

Eli Lilly and Co. 236

endometrial cancer 177

EPHB2 kinases 38, 60

ERB1/2 inhibitors. see also lapatinib

ERBB2 116, 117

ERBB3 298

ERK (extracellular signal regulated)kinases 38

erlotinib ix, 5, 81, 82, 83, 85, 127, 128

binding modes 98

mutations/drug resistance 139,

146–7

ETP-46464 192

everolimus ix, 127, 129, 151, 186

Exelixis 177

extracellular signal regulated kinases

38

F-12509a 197, 198

F317L gene 133, 134

fasudil 4, 5, 218, 221–2, 222

FDA (Food and Drug

Administration) approved

inhibitors ix

FGFR (fibroblast growth factor

receptor)

kinases 38, 63, 64, 64, 287

fibroblast growth faxtor 1 (FGFR1)

236

fibroblast growth faxtor 2 (FGFR2)63

FIKK (Plasmodium) kinases 271, 274,

280

Fit-3 89, 89

FKBP12 185–6

fluorescent resonance energy transfer

(FRET) 14

focused screen 9

fostamatinib 6, 227, 228

fragment-based lead generation

(FBLG) 70–3, 71, 72, 110

fragment docking 74

front pockets, solvent-exposed 91, 92

fructokinase 163

fructose biphosphate 2 (FBPase2)

163–4

funding, R & D 218

future developments 286, 298–9

kinase activation 296–7

magic bullets 295–6

overcoming resistance 286–95

polypharmacological inhibitors/

comination therapy 292–5

pseudokinases 297–8

G160E gene 145

G160V gene 145

G231W gene 133, 134

G719S gene 139, 140

galactokinase 164

gastrointestinal cancer 64, 117, 127,

132, 135, 295

gatekeeper mutations 133–4, 134

gatekeeper residues 83, 86, 116

Gates Foundation 262

GDC-0941 175–6, 177, 178, 181

GDC-0980 177

gefitinib ix, 5, 81, 82, 83, 85, 87, 127,

128

binding modes 98

efficacy 115

inhibitor selectivity 116

mutations/drug resistance 139, 140

solubility 91, 92

genetic mutations. see mutations/drug

resistance

Genentech 175, 177, 181

genomics, Plasmodium spp. 273–4

Gensia Sicor 169–70, 171

GHMP (galactokinase) 164

Gini coefficient 22, 23

GKA-22 252

GKA-50 252

glaucoma 221–2

Subject Index 307

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GlaxoSmithKline 179

Gleevec 5

GLPG0259 236

glucokinase, allosteric activators 244–

5, 259, 297

initial discovery 247–50

patent applications 254, 255–8, 259

recent advancements 250–4, 251,

252, 253, 254

structure/function 245–7, 246, 247,

248, 249, 250

Glu-Lys salt bridge 97, 99, 101

glutamic acid residues 70

glycine 62

glycolysis 162, 164, 201

GNE-477 177, 178, 178

GNF-5 102, 117, 294

GNF-7 137, 138

GP3269 169, 170

GP3966 170

GP515 169, 170

G-protein coupled receptors 91

GSK (glycogen synthesase) kinases 39

GSK1059615 179

GSK2126458 179, 179, 292, 293

GSK610677 227

GSK-856553 (losmapimod) 223, 226

H250Y gene 145

Her-2/3/4 kinases 39, 127, 139, 144,150, 151, 153

Herpes simplex virus 161, 165

hexokinases (HK) 162–3, 164. see also

glucokinase

high throughput screening (HTS) 9,

70

hinge region binding elements 65, 66,

69, 70, 82

hit identification cellular assays 89,

110–11

hit molecules22/23 70

hit rates, profiling experiments 16, 18

HKI-272 (neratinib) 142, 142, 287,

288

homology, structural 23, 63, 74, 80

hybridisation, structural 66–70, 68, 69

hydrogen bonding 71, 81

hydrophilicity 91

hydrophobic motifs 83, 85

binding modes 99

lead generation 61–4

mutations/drug resistance 134

IC50 values 103, 104, 105–6, 107, 117

inositol 1,4,5-triphosphate 3-kinase

(Itpk) 193–4

mevalonate kinase 200

p38 inhibitors 223, 224

phosphatidylinositol-3-kinases 182,

188, 189

P13K related kinases (PIKKS) 191,193

phosphatidylinositol-4-kinase

(P14K) 194

protein kinase family 109, 110, 114

pyruvate kinases 202

SK1/2 199

IC87114 183, 184, 185, 187

Icos 185

IGFR1 151, 152

IKKb 40, 223

IL-12 234

IL-1b 222

IL-23 234

IL-6 222, 232, 234

imatinib ix, 5, 58, 82, 83, 85, 88, 127

binding modes 100

chronic myeloid leukemia 219, 295

inhibitor selectivity 117

leukemia 126–7

mutations/drug resistance 131, 131,

132–9, 135

optimization of target modulation

291

polypharmacological inhibitors/

comination therapy 294

pulmonary arterial hypertension

237–8

structure 57, 238

imidazoquinoline 178

308 Subject Index

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immunology 127, 183, 231

immunosuppressants 193, 294, 296

in vitro to in vivo translation

JAK (Janus kinase) inhibitors 231–

2

malaria drugs 278–9

medicinal chemistry perspective

88–9, 90

mutations/drug resistance 144–7,

145, 146

P13K related kinases (PIKKS) 191

protein kinase family 96, 114–15,

117–18, 120

sphingosine kinase inhibitors 199

toxicity 219

inactive kinase conformations 57–8

INCB18424 234, 235

INCB28050 234, 235, 236

Incyte Corporation 234, 236

individualized approaches 291, 299

inflammatory bowel disease 223

inflammatory cytokines 229–30, 230–2, 234

inflammatory diseases 4, 6, 7. see also

rheumatoid arthritis

kinases under development 6

p38 inhibitors 222–7

phosphatidylinositol-3-kinases 183,

184–5

inflammatory pathways, compensa-

tory 223

inhibition mechanisms, protein kinase

family 97–109

inhibitors, small molecule 2, 3, 4, 5, 7.

see also specific

drugs by name

INK128 188

inositol 1,4,5-triphosphate 3-kinase

(Itpk) 193–4

inositol hexakiphosphate kinase

(IP6K) 194, 195

INS117548 222

insulin 151, 164

intellectual property 91–3. see also

patent applications

interaction map, dendrogram-based

81

Invitrogen 14, 30–53

Iressa 5

irreversability/reversibility 111–12,

117–18, 287–90

ischemia 218

isothermal titration 109

ITPK (inositol 1,4,5-triphosphate 3-

kinase) 193–4

JAK (Janus kinase) inhibitors 6, 36,

40, 230–6, 232, 298

JAK2V617F 298

JNK (stress activated protein) kinases

40, 103, 223

KC706 223

ketohexokinase (KHK) 163

Kinacia 182

Kinase Compound Set (KCS) 11

Kinaxo 15, 16

kinome, impact on medicinal chem-istry 1–8, 17, 26

approved inhibitors ix, 4, 5

chemical connectivity 16–21, 17,

19, 21, 26

classification 2

inflammatory diseases, inhibitors

under development 6, 7

kinase assay panels suppliers 11–

12, 30–53

non-human 263–4, 267–71, 268

scale assays 8–16, 9, 10

selectivity 21–6, 24, 25

Starts of Chemistry 9

tree plots 3, 218, 268

KINOMEscan 81, 83, 85

KIT kinase 41, 83, 87, 127, 135–6,

136. see also cKIT

knowledge based screen 9

KU-55933 192, 192

KuDOS Pharmaceuticals. see

AstraZeneca

Subject Index 309

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L308P gene 145

L790M gene 143

L858R gene 139, 140, 141, 143

lapatinib ix, 2, 4, 5, 18, 82, 83, 85, 128

binding modes 99, 101

inhibitor selectivity 116, 117

mutations/drug resistance 139, 140,

146–7, 151

lead generation 54, 75. see also Starts

of Chemistry

cellular assays 89

fragment-based 70–3, 71, 72, 110

hydrophobic motifs 61–4

inactive kinase conformations 57–8

isoform selective, pH domain

dependent Akt inhibitors 55, 55–6, 56

scaffold-hopping/hybridisation 66–70

structure-based design 66–74, 68

switch pocket inhibitors 58–61

targeted kinase libraries 65, 65–6,

66

virtual screening 73–4, 74

Leishmania major (cutaneous leish-

maniasis) 264, 265

leucine 61, 134, 137, 165

leucine-rich repeat kinases 41–2

leukemia 100, 117, 126–7, 132, 133,

187, 219, 295

Lexicon Pharmaceuticals 166, 167,167

libraries, kinase 65, 65–6, 66

Life Technologies 14

ligand efficiency 63, 70

Ligand Pharmaceuticals 224

ligand-protein binding 91

lipid kinases 173, 195–200, 202. see

also phosphatidylinositol-3-

kinases

lipophilicity 90–1

literature study, kinome tree plot 3

liver

cancer 120

toxicity 223

lonidamine 162, 163

losmapimod 6, 223, 226

LRRK2 (leucine-rich repeat) kinases

41–2

lung. see also pulmonary diseases

cancer 98, 115, 117, 119, 127, 139,

176, 238, 288

function 225, 238, 229

LY-2121260 251–2, 252

LY294002 173, 174, 175, 176, 177,

186, 189, 191, 192

lymphoma 179, 186, 187, 289

lysine 64

M351T resistance 133, 134

magic bullets 295–6

malaria 265–6, 266, 281

best practice/eradication agenda

272–3

boxes 280–1

drug discovery/development 271–2,

277–8, 279

drug specificity/safety 272

functional genomics 273–4

host kinases 274–5, 276

in vitro to in vivo translation 278–9

kinome 267–71, 268

Plasmodium structural biology

275–7

technical challenges 275–7

MAPK (mitogen-activated protein

kinases) 42, 149, 220. see also

MEK

MAPKAPK5 (mitogen-activated

protein kinase activated pro-

tein) kinase 5 236

Markov model 1

medicinal chemistry perspective 79–

80, 93. see also

kinome; mutations/drug resis-

tance; non-cancer

applications

in vitro to in vivo translation 88–9,

90

intellectual property considerations91–3

310 Subject Index

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selectivity effects 80–8, 82, 83, 84,

85, 86, 87, 88

solubility 80, 90–1, 91

Medicines for Malaria 262

MEK (mitogen activated protein

kinase) 87, 293. see also

MAPK

binding modes 101

inhibition mechanisms 103

and phosphatidylinositol-3-kinases

178–9

resistance mechanisms not invol-

ving kinase domain 148

melanoma 101

Merck & Co 293

MET kinase 43, 140, 275. see also

cMET kinases

Metabasis 169–70, 171

methyl group, CDK inhibitors 90

mevalonate (MK) kinase 200, 200–1

Michael addition reaction 101, 101

Michaelis-Menten constant 104, 139

microglial cells 224

Millipore 13, 30–53

mitogen activated protein kinase. see

MAPK; MEK; MSK

MK-0457 138

MK2206 56

MLK1/2/3 (mixed lineage) kinases 43,223

MSK (mitogen and stress-activated

protein) kinases 10, 24 , 36, 44,

221

mTOR (mammalian target of rapa-

mycin) kinase ix, 127, 296

mutations/drug resistance 151, 152

and phosphatidylinositol-3-kinases173, 178, 179, 180, 185–9, 191, 200

polypharmacological inhibitors/

comination therapy 292

multikinase inhibitors 116, 236, 237

mutations/drug resistance 119, 120,

126–9, 132, 143, 151–3

BCR-ABL kinases 133–5, 134, 144,153

design strategies to overcome 136–

9, 137, 141–5, 142, 143, 144, 286–7

EGFR kinases 139–44, 140, 142,

143

imatinib 132–9

irreversible inhibitors 287–90

kinase activation 129–31, 130, 131

mechanisms not involving kinase

domain 147–51, 148, 149, 150, 152

Kit kinase 135–6, 136

optimization of target modulation

290–2

preclinical prediction 144–7, 145,

146

type 1/II/III inhibitors 131–2

myocardial infarction 185

N,N-di-methyl sphingosine 197

N822K gene 136

Nanosyn assay panels 14, 30–53

Neglected Tropical Diseases 262

neratinib 142, 142, 287, 288

neuropathic pain 224, 226

Nexavar 5

nilotinib ix, 5, 82, 83, 117, 127, 134,

238

binding modes 100

gastrointestinal stromal tumors 136

kinase activation 131, 131

mutations/drug resistance 132–3,

135, 147

polypharmacological inhibitors/comination therapy 294

pulmonary arterial hypertension

237–8

NIMA (never in mitosis/Aspergillus)

kinases 269–70

NMR (nuclear magnetic resonance)

109

non-cancer applications of kinaseinhibitors 218–20, 239.

see also glucokinase

BCR-ABL, c-Kit, PDGFR inhibi-

tors 237–8

JAK kinase inhibitors 230–6

Subject Index 311

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MAPKAPK5 inhibitors 236

multikinase inhibitors 236, 237

p38a inhibitors 222–7, 225

PKC inhibitors 229–30, 230

Rho kinase inhibitors 221–2, 222

SYK (spleen tyrosine kinase) 227–

9, 228

non-Hodkin’s lymphoma 176

non-homologous end joining 189

non-protein kinases 161–2, 202–3

lipid kinases 173, 202. see also

phosphatidylinositol-3-kinases

mevalonate kinase 200, 200–1

nucleoside kinases 164–72, 169,170, 171, 172, 202

pantothenate kinase 202

pyruvate kinases 201–2

sugar kinases 162–3, 163, 202

non-small cell lung cancer 127, 139,

176, 288

nonspecific inhibition 111

Novartis 178, 229, 235

N-RAS activation 149

NU7441 191, 192

nuclear magnetic resonance (NMR)

109

nucleoside kinases 170, 172, 202

analogs 168

non-protein kinases 164–72, 169,

171

NVP-231 197

NVP-BEZ235 292

oncogene addiction 119

oncology. see cancer. see also specific

cancers by name

Oncoththyreon 174

1KV2 crystal structure 59, 60

ONO12380 138, 139

ORAL solo study, rheumatoid

arthritis 232–3

OSI Pharmaceuticals 187

OSI-027 187

OSKIRA (Oral Syk Inhibition in RA)

228

other-orphan kinases 270

ovarian cancer 150

overlayed kinase crystal structures 68

oxazolidine 199

oxygen radicals 135

P13K. see phosphatidylinositol-3-

kinases

P110alpha kinase 149

P124L gene 149

P124Q gene 146

P124s gene 146

P13 kinase. see phosphatidylinositol-

3-kinases

P38 kinases 7, 25, 45, 59, 60, 114, 120,

127

binding modes 100, 102, 103

BIRB-796 58, 59

inhibition mechanisms 103

non-cancer applications 222–7

pharmacokinetic properties 223–4

structure 225

P38-MAP kinase 58, 83, 108–9

P85 binding 150

pain, neuropathic 224, 226

Palomid 529 188

pamapimod 6, 223

pancreatic cancer 117, 186

pankinase inhibitors 98, 116

pantothenate kinase 202

parasitic diseases 262–3, 281. see also

malaria

kinetoplastids 264–5

non-human kinomes 263–4

Trypanosoma kinomes 265

Parke Davis inhibitors 142

partition index, thermodynamics-

based 23

patent applications 2, 67, 91–3, 218

glucokinase 254, 255–8, 259

inositol 1,4,5-triphosphate 3-kinase193–4

patient selection 119–20

pazopanib ix, 5, 236, 237

PCI-32765 287, 288, 289

312 Subject Index

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PCR (polymerase chain reactions)

152

PD166326 82, 83

PD334581 87, 88

PDGFR (platelet-derived growth

factor receptor) 45–6, 89, 89,

135, 295. see also pazopanib

inhibitor selectivity 117

mutations/drug resistance 132, 153

pulmonary arterial hypertension

237–8

receptors 236

signaling pathways 149

PDK1(phosphoinositide-dependent)

kinases 46

activators 297

inhibitors 70, 71, 72, 73

mutations/drug resistance 149

structure 72

PDP 1PKG 83

PDP 2GOE 83

PF-00299804 142, 287

PF-04691502 180

PF-0497064 180

PfCDPK1 269, 278, 279

PfGSK1 278, 279

Pfizer 188, 225, 229, 235

PFK2 (6-phosphofructo-2-kinase)

163–4

Pfmap2 276, 277

PfNEK-1/2/3 269–70

PfPK5 276, 277, 278, 279

PfPK7 276, 277, 278, 279, 279

PfPK9 270

PfPKA 267

PfUBC13 270

PGE2 (prostaglandins) 224

pH domain dependent Akt inhibitors

55, 55–6, 56

PH-797804 6, 223, 224–6, 227

pharmacophore-based methods 73

Phe-489 64

phenylalanine 63, 83, 99, 134, 188

phloretin analogs 162

phosphatidylinositol-3,4,5-tripho-

sphate (PIP3) 129

phosphatidylinositol-3-kinases

(P13K) 46–7, 144, 150, 151,

200, 202

IC50 values 182

inhibitors 292

inositol 1,4,5-triphosphate 3-kinase

193–4

and mTOR kinase inhibitors 173,

178, 179, 180, 185–9, 191, 200

mutations/drug resistance 151, 152

signaling pathways 149

structure 174, 175, 176–81

phosphatidylinositol-3-kinases

related kinases (PIKKS) 189–

93

phosphatidylinositol-4-kinase (P14K)

194, 194

phosphatidylinositol-4-phosphate 5-kinase (PPP5K) 194–5

phosphoenolpyruvate 201, 201

phosphoinositide-dependent kinase.

see PDK1

PIK. see phosphatidylinositol kinases

PIK-293 184, 187

PIK-39 183, 184, 184, 187

PIK3CA gene 150, 179, 182

PIKfyve 194, 195

pirfenidone 129

PK. see protein kinase

PKAN (pantothenate) kinase 202

PKI-179 181

PKI-587 180

Plasmodium falciparum. see malaria

platelet-derived growth factor recep-

tor. see PDGFR

pleckstrin homology 102, 149

PLK1 (Polo-like kinases) 25, 25, 48,

145

PLX4032 101

PLX-4032 149, 149, 290

polymerase chain reactions (PCR)

152

polypharmacological inhibitors 292–5

Subject Index 313

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Portola Pharmaceuticals 229

PP242 189

PPY-A 138

prevention of activation 103

PRK. see protein kinases

PRKWNK1 kinase 275

profiling experiments 17, 17–18, 20,

22, 23

Proquinase kinome assay panels 13,

30–53

prostaglandins (PGE2) 224

prostate cancer 188, 189

protein binding partners 15–16

protein kinase family 48, 80, 96, 120–

1, 221

ATP-dependence 104–5, 105, 106,

115, 115, 116, 120

binding assays 107–9

binding modes 97–101, 99, 100,

101, 101–3, 102

classification 1, 2

clinical applications 114–20

combination therapy 117

covalent inhibition 114, 118–19

evaluation of inhibitors 111–12

hit identification assays 110–11

IC50 values 109, 110, 114

inhibition mechanisms 97–103

inhibition rates of onset/reversal

105–6

inhibitor selectivity 116–17

kinetics of inhibition 103–9

mutant kinase inhibition 119, 120

non-activated kinases 118

non-human kinomes 263–4

patient selection 119–20

PKA 47, 97, 98, 221

PKB 24, 25, 31, 54, 55, 55–6, 56,

152, 267, 293

PKC 47–8, 229–30, 230

PKCzeta kinase 275

PKG 48, 267

SAR similarity 112–13, 114

slow binding/tight binding/covalent

inhibition 114

slowly reversible/irreversible inhi-

bitors 117–18

structure-based design 113–14

3-D structure 97, 98

tight binding inhibition 106–7

protein-ligand docking 70, 73, 74

protein stabilization 108

PRT-062607 229

pseudokinases 297–8

PSN-GK1 250

psoriasis 223, 224, 229–30, 234, 235

PTEN pathway 149–50, 150, 151, 183

PTGS1 gene 135

pulmonary inflammatory diseases 225

pulmonary arterial hypertension 237–

8

pulmonary fibrosis 127

Purfalcamine 2 278, 279

purine 98, 99, 100, 116, 120

PX-866 174, 181

pyrazolopyrimidine inhibitors 189

pyridinone fragments 71

pyridinyl imidazoles 7, 108

pyridonepyrimidines 180, 181

pyridopyrimidines 168

pyruvate kinases 201–2

QSAR model 170

quercetin 173

quinoxaline 177, 181

R & D funding 218

R406 227–8

R59022 195

R59949 195

R935788 (fostamatinib) 6, 227, 228

RAD001 178

RAF (rapidly accelerated fibrosar-

coma) kinases 48–9, 117, 147,

148. see also BRAF; CRAF

rapamycin 127, 186, 189, 294, 296

comparison with P13K 178, 187,

188, 192

mutations/drug resistance 149, 151

314 Subject Index

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polypharmacological inhibitors/

comination therapy 292

RAS-independent signaling pathways

147, 148

Reaction Biology (RBC) kinome

assay panels 13, 30–53

reactive oxygen species (ROS) 135

renal cancers 120, 127, 186

renal transplant patients 230, 233

resistance. see mutations/drug resis-

tance

retimoic acid 202

reversibility/irreversibility 111–12,

117–18, 287–90

rheumatoid arthritis 6, 7, 58, 224, 228

JAK inhibitors 232–3, 234, 235

MAPKAPK5 inhibitors 236

p38a inhibitors 223

Rho kinase (Rock) 4, 10, 24, 49, 221–

2, 222

ribosomal S6 kinases 36, 49–50, 221

ridaforolimus 186

RO28-1675 250, 253

RO4402257 (pamapimod) 6, 223

Roche 247

ROS (reactive oxygen species) 135

RSK1/2 (ribosomal S6) kinases 36,

49–50, 221

S enantiomer 199

S-15183a/b 197

S6K feedback loop 151, 152

safety. see toxicity

salt bridges, Glu-Lys 97, 99, 101, 186

SANK71896 197

Sanofi-Aventis 177

Santen Pharmaceuticals 221–2

SAP (stress activated protein) kinases

40, 103, 223

SAR similarity 18, 19, 20, 70, 111. see

also selectivity

Abbott inhibitors 168

kinome tree plot 3

losmapimod 226

phosphatidylinositol-3-kinases

related kinases 191

protein kinase family 106, 112–13,

114

SB-203580 7

scaffold-hopping 66–70, 68

scale assays, kinome 8–16, 9, 10

Schisandrin B 193

Scientists Against Malaria (SAM) 277

SCIO-469 223

screening 80

selectivity 20, 54, 57, 58, 60

JAK inhibitors 234

magic bullets 295–6

measures 21–6, 24, 25

p38 inhibitors 223–4, 226

phosphatidylinositol-3-kinases 185

phosphatidylinositol-3-kinases

related kinases 189

pockets 70, 83, 98, 99, 100, 100, 116

protein kinase family 98, 99, 100,

100, 102, 115, 116–17

Rho kinase 221

scores 81

structural basis 80–8, 82–8

and toxicity 219

selumetinib 179

Senju Pharmaceuticals 221–2

serine 160 71, 72

serine/threonine protein kinases 51

SF1126 175, 181

SFK-86002 60

SGK(serum/glucocorticoid regulated)kinase 50–1, 275

SGX-70393 138

side-effects 5–6, 80, 88, 277

Signalchem kinome assay panels 13,

30–53

signaling pathways 26, 88, 129

JAK inhibitors 230–1, 235

non-human kinases 276

p38a inhibitors 226, 227

phosphatidylinositol-3-kinases 183

protein kinase family 116, 120

Subject Index 315

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resistance not involving kinase

domain 147–51, 152

sphingosine kinase inhibitors 197

SILAC (Stable Isotope Labelling by

Amino Acids in Cell culture)

16

sirolimus ix, 127, 129

SK1/2 197, 199

SK1-I 197, 198, 198, 199

SK1-II/III/IV 199

SKF-86002 59, 60

slow binding protein kinase family

114

small molecule

glucokinase activators. see gluco-kinase

inhibitors 2, 3, 4, 5, 7. see also

specific drugs by name

SNJ-1656 222

solubility 80, 90–1, 91

solvent channel units 70

solvent-exposed front pockets 91, 92

sorafenib ix, 5, 57, 58, 82, 83, 85, 89,

127, 128

binding modes 100

in vitro to in vivo translation 89

inhibitor selectivity 116, 117

kinase activation 131, 131

patient selection 120

sotrastaurin 229, 230

specificity, non-cancer applications

219, 272. see also selectivity

sphingosine kinase 196, 196, 197–200,

198

spleen tyrosine kinases. see SYK

Sprycel 5

SRC kinase 51, 126

Starts of Chemistry 8, 9, 10, 16–21.

see also lead generation

STK (serine/threonine protein)

kinases 51

STK35 kinase 275

Structural Genomics Consortium130, 131, 277

structure ix, 4, 24. see also individual

kinases/inhibitors by name; X-

ray crystallography

structure-based design 120

lead generation 66–74, 68, 69

protein kinase family 97, 98, 113–

14

SU11752 192, 192

sub-arachnoid hemorrhage 218, 221

subependymal giant cell astrocytomas186

sugar kinases 162–3, 163, 202. see also

glucokinase

sunitinib ix, 4, 5, 81, 82, 83, 85, 87,

127, 128

gastrointestinal stromal tumors

135, 136

inhibitor selectivity 116

kinase activation 131, 131

SW13 184, 187

SW30 187

switch pocket inhibitors 58–61

SYK (spleen tyrosine) kinases 6, 51,

227–9, 228

synthetic tractability 70

systemic lupus erythematosus 193

systemic sclerosis 238

T3151 gene 61, 117, 133, 134, 135,

137, 141, 147

T7 bacteriophages 81

T790M gene 141, 143–4, 146

tailored approaches 291, 299

TAK1 (TGF-beta activated kinase 1)

kinases 51, 223

tarceva 5

Taregen 185

target definition compounds (TDCs)

108

target hopping 20

Target Product Profiles 271

target validation 7

targeted kinase libraries, lead genera-

tion 65, 65–6, 66

Tasigna 5

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tasocitinib 6, 231–2, 233–4

taxol 176

TCMDC-133396/133561/141334 279

temsirolimus ix, 127, 129, 151, 186

tethering with extenders technique 70,71, 72

TGF-beta activated kinase 1 (TAK1)

51, 223

TGFbR1 (transforming growth fac-

tor-b type 1) 68, 69

TG100-115 185, 187

TGX-221 182, 187

TGX-286 187

thermodynamics-based partition

index 23

3-bromopyruvate 162–3

3-D structure. see structure-baseddesign

threonine 83, 133, 136

Threshold Pharmaceuticals 162

Thrombogenix 182

thymidine kinase 161, 165–6

thyroid cancer 117

TIE (tyrosine with Ig and EGF

homologous domains) kinases

25, 52

tight binding inhibition 106–7, 114.

see also reversibility

TK. see tyrosine kinases

TKL (tyrosine kinase-like) kinases264, 270, 274

TNF-a 222, 223, 224

tocilizumab 232, 234

Topo II 193

TORC1/2 188, 189

Torin1 188

toxicity

liver 223

malaria drugs 272

and specificity 219

transforming growth factor-b type 1

(TGFbR1) 68, 69

Transitional Dyspnoea Index 225

trastuzumab 150, 151, 177

mutations/drug resistance 149, 175

and phosphatidylinositol-3-kinases

179

tree plots, kinome 3, 218, 268

Trypanosoma spp. 264, 265

tuberous sclerosis 186

Tumor M2-PK 201

2,4-diamino pyrimidine kinase inhi-bitors 20, 21

tykerb 5

type 1 inhibitors 81, 82, 84, 91–3,

131–2

type II inhibitors 81–2, 83, 84, 89, 93,

131–2

type III inhibitors 86–7, 88, 89, 93,

131–2

tyrosine kinase-like kinases (TKL)

264, 270, 274

tyrosine kinases 2, 8. see also BCR-ABL kinases

inflammatory diseases 6

inhibitors 2, 127

non-human kinomes 263

PDGFRalpha 135

tyrosine with Ig and EGF homolo-

gous domains kinases 25, 52

U-0126 120

U87MG mouse model 188

UBC13 270

UBV radiation 147

ulcerative colitis 234

un-targeted kinome 26

uridine-cytidine kinase 161, 164–5,165

ustekinumab 234

V560G gene 136, 146, 149

V600E gene 147

V6545A gene 136

valine 134, 136

vandetanib ix, 81, 82, 117

variability, individual patients 291,

299

VE-821 192, 193

Subject Index 317

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VEGFR (vascular endothelial growth

factor receptor)

kinases 89, 89, 117, 178, 236. see

also pazopanib;

vandetanib

Vertex Pharmaceuticals 67–8, 234

virtual screening 73–4, 74vitamin B6 202

votrient 5

VX-509 234

VX-680 137, 145

VX-702 7, 223

VX-745 223

Warburg hypothesis 162websites

Arqule 61

Carna 14

Cell Signaling Technology 2

Deciphera pharmaceuticals 58

Kinaxo 16

kinome assay panels 12

Life Technologies/Invitrogen 15lymphoma study 289

Millipore 13

Nanosyn 14

Neglected Tropical Diseases 262

Proquinase 13

Reaction Biology 13

Scientists Against Malaria 277

Signalchem 13

websites 14

wortmannin 173, 174, 175, 186WYE-125132 188–9, 190

Wyeth 142, 188

WZ4002 101, 101, 101, 119

XL147 177

XL765 177

X-ray crystallography 18, 23, 26, 70,

71. see also structure; and see

individual kinases/inhibitors by

name

Y156H gene 145

Y253 gene 147

Y253F gene 134, 134

Y-39983 222

Y823D gene 136

ZM-447439 144–5, 145

zotarolimus 127, 129

318 Subject Index

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