Pharmacological influence of signaling
description
Transcript of Pharmacological influence of signaling
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
PHARMACOLOGICAL INFLUENCE OF SIGNALING
Tímea Berki and Ferenc BoldizsárSignal transduction
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
Potential drug targets in signaling pathways
PIP2 PIP3 PIP2PIP3
PI3K AKTPDK PTEN
Ribosome protein rRNA↑ Translation
S
M
G2G1
↑ Cell cycle
Cyclin D Cyclin A,ECyclin D
Cyclin B
GRB2SOSRAS
RAF
MEK1/2
MAPK1,2,3
GTP GDP
RAS
Specific gene products
Receptor and nonreceptortyrosine kinases
G-proteincoupled receptors
PLC PKC
AC PKA
G protein
ATFc-Jun c-Myc NF-IL6
Nucleus
4-EBP p70S6
mTOR
B
A
C
D
E
F
CDK4, 6 CDK2
CDK1
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Various levels of intervention I
Protein
RNADNA
ProteolysisB ACD
E
F
G
P
Substrate
ATP
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Various levels of intervention II• Blockade of cell surface receptors• Inhibition of signal transmission (eg. kinase
inhibitors)• Interference with the turnover of signaling
proteins (eg. proteosomal degradation, siRNS)
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Blockade of surface receptors with monoclonal antibodiesAntibody Brand name Approval
dateType Target Indication
Adalimumab Humira 2002 Human Inhibition of TNF- signalingα Several auto-immune disorders
Bevacizumab Avastin 2004 HumanizedVascular endothelial growth factor (VEGF)
Colorectal cancerAge related macular degeneration
Cetuximab Erbitux 2004 ChimericEpidermal growth factor receptor
Colorectal cancerHead and neck cancer
Infliximab Remicade 1998 Chimeric Inhibition of TNF- signalingα Several autoimmune disorders
Panitumumab
Vectibix 2006 HumanEpidermal growth factor
receptorColorectal cancer
Ranibizumab Lucentis 2006 HumanizedVascular endothelial growth factor A (VEGF-A)
Macular degeneration
Rituximab Rituxan 1997 Chimeric CD20 Non-Hodgkin lymphoma
Tositumomab Bexxar 2003 Murine CD20 Non-Hodgkin lymphoma
Trastuzumab Herceptin 1998 Humanized ErbB2 Breast cancer
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Selected kinase inhibitors in clinical development
Target Agent Structure Develpoment stage
Growth-factor-receptor inhibitors
EGFR
IMC-C225 cetuximab (Erbitux, Imclone)ABX-EGF (Abgenix)EMD 72000 (Merck KgaA Darmstadt)RH3 (York Medical Bioscience)ZD1839 gefitinib (Iress; AstraZeneca)MDX-447 (Medarex/Merc KgaA)OSI-774 eriotinib (Tarceva; OSI-Pharmaceuticals)CI-1033/PD183805 (Pfizer)EKB-569 (Wyeth Ayerst)GW2016/572016 (GlaxoSmithKLine)
Monoclonal antibodyMonoclonal antibodyMonoclonal antibodyMonoclonal antibodyMonoclonal antibody bivalentSmall-molecule kinase inhibitorSmall-molecule kinase inhibitor
Small-molecule kinase inhibitorSmall-molecule kinase inhibitorSmall-molecule kinase inhibitor
Phase IIIPhase IIPhase IPhase IIPhase IPhase IIIPhase III
Phase IIPhase IPhase I
HER2/neu
Trastuzumab (Herceptin; Genentech)MDX-210 (Medarex/Novartis)2C4 (Genentech)17-AAG (Kosan)
Monoclonal antibodyMonoclonal antibodyMonoclonal antibodyeldananycin derivate inhibits HSP90
RegisteredPhase IPhase IPhase I
PDGFR/c-Kit/BCR-ABL Imatinib (STI571/Gleevec; Novartis) Small-molecule kinase inhibitor Registered
Ras inhibitors Ras
ISIS 2503 (Isis Pharmaceuticals)R115777 (Johnson and Johnson)SCH66336 (Schering-Plough)BMS214662 (Bristol-Myers-Squibb)
Antisense oligonucleotideFarnesyl transferase inhibitorFarnesyl transferase inhibitorFarnesyl transferase inhibitor
Phase IIPhase II/Phase IIIPhase IIPhase II
Raf inhibitors RafISIS 5132/CGP698-46AL-779, 450 (Merck)BAY 43-9006 (Onyx/Bayer)
Antisense oligonucleotideSmall-molecule kinase inhibitorSmall-molecule kinase inhibitor
Phase II
Phase II
MEK inhibitors MEKPD 184352/CI-1040 (Pfizer)U-0126 (Promega)
Small-molecule kinase inhibitorSmall-molecule kinase inhibitor
Phase IIPhase I
mTOR inhibitors mTOR
CCI-779 (Wyeth)RAD001 (Novartis)
Rapamacyn/sirolimus (Wyeth)
Inhibits mTOR kinase by binding to FKBP12Inhibits mTOR kinase by binding to FKBP12
Inhibits mTOR kinase by binding to FKBP12
Phase IIPhase I as a cancer therapeuticPhase II/III as an immunosuppressantRegistered as an immunosuppressant
Cyclin-dependent-kinase inhibitors
CDK
Flavopirodol/HMR-1275 (Aventis)E7070 (EISAI)CYC202 (Cyclacel)BMS-387032 (Bristol-Myers-Squibb)
Small-molecule kinase inhibitorSmall-molecule kinase inhibitorSmall-molecule kinase inhibitorSmall-molecule kinase inhibitor
Phase IIPhase IPhase IPhase I
Other targets and agents
PKC
ISIS 3521/LY900003 Affinitak (Isis Pharmaceuticals)CGP41251PKC412 (Novartis)Bryostatin-1 (GPC Biotek)UCN-01 (Kyowa Hakko Kogyo)
Antisense oligonucleotide
Staurosporine analogueSmall-molecule kinase inhibitorStaurosporine analogue
Phase III
Phase IIPhase IIPhase I/II
PKC-b LY333531 (BI Lilly) Small-molecule kinase inhibitorPhase I oncologyPhase II/III diabetic neuropathy
PDK1 UCN-01 (Kyowa Hakko Kogyo) Staurosporine analogue Phase I/II
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Calcineurin and rapamycin
R
FKBP12
FK506
FKBP12
Cell-cycleTranslation
mTOR
FRB
CyPA
CsA
Cation stressT-cell activation
Calcineurin A
B
CaM
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Rapamycin
Apoptosis
PI3K
AKT
Bcl-2
p70S6KPHASI
P27kip1
G1 S phase
mTOR
?
a gb
IL2
IL2R
R FKBP12
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Toll-like receptor inhibitors
MyD88 TRIF
TLR3TLR7
TLR2
PKA
SP600125SB203580
U0126
PD98059
H-89
Celastrol
Bay11-7082
2-Aminopurine
PepinhTRIFPepinhMYD
TAK1 PKR
p38 JNK
MKKs lkBp50
p65
MyD88
Polymixin B
CLI095
LPS
TLR4
MyD88
MD2LBP
dsRNA
BX795TBK1IKKe
MDA-5RIG-1
IPS1
TLR9
Chloroquine
JAK2
Wortmannin
Rapamycin
LY294002
AG490
mTOR
PI3K
CD14
OxPAPC
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ERB signaling intervention
Tyrosine kinase inhibitors(e. g. tryphostins)
Unfolded, inactiveErbB dimer
ErbB dimerLigand
Hsp90 inhibitors(e. g. geldanamycin)
Hsp90Phosphoproteins and
downstream signalling events
Anti-ErbB antibody(e. g. Herceptin)
Nucleus
ErbB gene
Immature ErbB
ER/Golgi
Translation
Triplex-forming oligos,antisense oligos
Ribozymes
Transcription
scFvs
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Proteosome inhibitors-Bortezomib
Bortezomib
Cytokines activatecell-surface receptors
↓ Cytokines
P105 precursorprocessed
Proteasome
Degraded IκB
Activated NF-kB translocatesto the nucleus
↓ Anti-apoptoticfactors
Activation of NF-kBby degradation of IkB
↓ Inflammatorymolecules
lkBp50
p65
p105
↓ Cell adhesionmolecules
p50
lkBp65
p50
p65
Nucleus
NF-kB activatestranscription
p50
p65NF-kB
O H OH
N
N
O
N BNH
OH
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Apoptosis signaling intervention
Chemotherapy
DNA damage
Bcl-2 inhibitors
IAP inhibitors
TRAIL
DR4/DR5
HDAC inhibitors
Bcl-2Bcl-XL
Bfl-1/A1c-FLIPDcR1
Proteasome
c-FLIP
Caspase-9Cytc
Caspase-8
APOPTOSIS
Bcl-2 Bcl-xL
BakBax
c-IAP1c-IAP2XIAP
p53
tBid Pro-caspase-3
NF-kB
IAPs
lkBP
P
Caspase-3
Bid
Proteasomeinhibitors
lkB
NF-kB
FADD
Smac/Diablo
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HSP-90 inhibitors
Ubiquitin ligase CHIP
Proteasome
Ubiquitin proteasome-dependent degradation
Early complex
HSP40HSP70
CLIENT
Intermediate complex
HSP90
HSP90
HSP40HSP70
HOPCLIENT
CLIENTUBUB UBUBUB
HSP90
HSP90
Geldanamycin binds to theATP-binding site of HSP90
ATPADP
Mature complex
HSP90
HSP90
CLIENTCDC37
p23Immunophilin
HARCAH1
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