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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

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(1)

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(2)

PHARMACOLOGICAL INFLUENCE OF

SIGNALING

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

Potential drug targets in signaling pathways

PIP

2

PIP

3

PIP

3

PIP

2

PI3K PDK AKT PTEN

Ribosome protein rRNA

↑ Translation

S

M

G2 G1

↑ Cell cycle

Cyclin D Cyclin D Cyclin A,E

Cyclin B GRB2

SOS RAS

RAF

MEK1/2

MAPK 1,2,3

GTP GDP

RAS

Specific gene products

Receptor and nonreceptor tyrosine kinases G-protein

coupled receptors

PLC PKC

AC PKA

G protein

ATF c-Jun c-Myc NF-IL6

Nucleus

4-EBP p70S6 mTOR

B A

C

D

E

F

CDK4, 6 CDK2

CDK1

(4)

Various levels of intervention I

Protein

RNA DNA

Proteolysis

B A

C D

E

F

G

P Substrate

ATP

(5)

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)

(6)

Blockade of surface receptors with monoclonal antibodies

Antibody Brand name Approval date Type Target Indication

Adalimumab Humira 2002 Human Inhibition of TNF-α signaling Several auto-immune disorders

Bevacizumab Avastin 2004 Humanized Vascular endothelial growth factor (VEGF)

Colorectal cancer Age related macular degeneration

Cetuximab Erbitux 2004 Chimeric Epidermal growth factor

receptor Colorectal cancer

Head and neck cancer Infliximab Remicade 1998 Chimeric Inhibition of TNF-α signaling Several autoimmune

disorders Panitumuma

b Vectibix 2006 Human Epidermal growth factor

receptor Colorectal cancer Ranibizumab Lucentis 2006 Humanized Vascular 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

(7)

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 antibody Monoclonal antibody Monoclonal antibody Monoclonal antibody Monoclonal antibody bivalent Small-molecule kinase inhibitor Small-molecule kinase inhibitor Small-molecule kinase inhibitor Small-molecule kinase inhibitor Small-molecule kinase inhibitor

Phase III Phase II Phase I Phase II Phase I Phase III Phase III Phase II Phase I Phase I

HER2/neu

Trastuzumab (Herceptin; Genentech) MDX-210 (Medarex/Novartis) 2C4 (Genentech)

17-AAG (Kosan)

Monoclonal antibody Monoclonal antibody Monoclonal antibody

eldananycin derivate inhibits HSP90

Registered Phase I Phase I Phase 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 oligonucleotide Farnesyl transferase inhibitor Farnesyl transferase inhibitor Farnesyl transferase inhibitor

Phase II Phase II/Phase III Phase II Phase II

Raf inhibitors Raf ISIS 5132/CGP698-46A

L-779, 450 (Merck) BAY 43-9006 (Onyx/Bayer)

Antisense oligonucleotide Small-molecule kinase inhibitor Small-molecule kinase inhibitor

Phase II Phase II

MEK inhibitors MEK PD 184352/CI-1040 (Pfizer)

U-0126 (Promega) Small-molecule kinase inhibitor

Small-molecule kinase inhibitor Phase II Phase I

mTOR inhibitors mTOR

CCI-779 (Wyeth) RAD001 (Novartis) Rapamacyn/sirolimus (Wyeth)

Inhibits mTOR kinase by binding to FKBP12 Inhibits mTOR kinase by binding to FKBP12 Inhibits mTOR kinase by binding to FKBP12

Phase II

Phase I as a cancer therapeutic Phase II/III as an immunosuppressant Registered as an immunosuppressant Cyclin-dependent-kinase

inhibitors CDK

Flavopirodol/HMR-1275 (Aventis) E7070 (EISAI)

CYC202 (Cyclacel)

BMS-387032 (Bristol-Myers-Squibb)

Small-molecule kinase inhibitor Small-molecule kinase inhibitor Small-molecule kinase inhibitor Small-molecule kinase inhibitor

Phase II Phase I Phase I Phase 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 analogue Small-molecule kinase inhibitor Staurosporine analogue

Phase III Phase II Phase II Phase I/II

PKC-b LY333531 (BI Lilly) Small-molecule kinase inhibitor Phase I oncology

Phase II/III diabetic neuropathy

PDK1 UCN-01 (Kyowa Hakko Kogyo) Staurosporine analogue Phase I/II

(8)

Calcineurin and rapamycin

R FKBP12

FK506 FKBP12

Cell-cycle Translation

mTOR FRB CyPA

CsA

Cation stress T-cell activation

Calcineurin A B

CaM

(9)

Rapamycin

Apoptosis PI3K

AKT

Bcl-2

p70S6K PHASI

P27

kip1

G1 S phase

mTOR

? a b g

IL2

IL2R

R FKBP12

(10)

Toll-like receptor inhibitors

MyD88 TRIF

TLR3 TLR7

TLR2

PKA

SP600125 SB203580

U0126 PD98059 H-89

Celastrol Bay11-7082 2-Aminopurine PepinhTRIF PepinhMYD

TAK1 PKR

p38 JNK

MKKs lkB

p50 p65 MyD88

Polymixin B

CLI095 LPS

TLR4

MyD88 MD2 LBP

dsRNA

BX795 TBK1

IKKe

MDA-5 RIG-1

IPS1 TLR9

Chloroquine

JAK2

Wortmannin

Rapamycin LY294002

AG490

mTOR PI3K CD14

OxPAPC

(11)

ERB signaling intervention

Tyrosine kinase inhibitors (e. g. tryphostins)

Unfolded, inactive ErbB dimer ErbB dimer

Ligand

Hsp90 inhibitors (e. g. geldanamycin) Hsp90

Phosphoproteins 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

(12)

Proteosome inhibitors-Bortezomib

Bortezomib

Cytokines activate cell-surface receptors

↓ Cytokines

P105 precursor processed

Proteasome

Degraded IκB

Activated NF-kB translocates to the nucleus

↓ Anti-apoptotic factors Activation of NF-kB

by degradation of IkB

↓ Inflammatory molecules lkB p50

p65 p105

↓ Cell adhesion molecules p50

lkB p65

p50 p65

Nucleus

NF-kB activates transcription p50

p65 NF-kB

O H OH

N N

O

N B

N

H OH

(13)

Apoptosis signaling intervention

Chemotherapy

DNA damage Bcl-2 inhibitors

IAP inhibitors TRAIL DR4/DR5

HDAC inhibitors

Bcl-2 Bcl-XL Bfl-1/A1

c-FLIP DcR1 Proteasome

c-FLIP

Caspase-9 Cytc

Caspase-8

APOPTOSIS Bcl-2 Bcl-xL

Bak Bax

c-IAP1 c-IAP2 XIAP p53

tBid Pro-caspase-3

NF-kB

IAPs

lkB P P

Caspase-3 Bid

Proteasome inhibitors

lkB NF-kB

FADD

Smac/D

iablo

(14)

HSP-90 inhibitors

Ubiquitin ligase CHIP

Proteasome

Ubiquitin proteasome-dependent degradation

Early complex

HSP40 HSP70

CLIENT

Intermediate complex

HSP40 HSP70 HOP

CLIENT

CLIENT UB UB

UB UB UB

Geldanamycin binds to the ATP-binding site of HSP90 ATP

ADP

Mature complex H

S P 9 0

H S P 9 0

CLIENT CDC37 p23 Immunophilin

HARC AH1

+

Hivatkozások

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