Pharmacological influence of signaling

1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Pharmacological influence of signaling

3. Potentialdrugtargetsinsignalingpathways G-protein coupledreceptors Receptor and nonreceptor tyrosinekinases A S mTOR PIP2 PIP3 PIP3 PIP2 RAS RAS SOS GRB2 RAF PI3K PDK AKT G1 G2 4-EBP p70S6 PTEN GTP GDP G protein MEK1/2 M PKC PLC E C B MAPK1,2,3 AC PKA D F ↑ Translation Ribosome protein rRNA ↑ Cellcycle CDK4, 6 CDK2 c-Jun c-Myc NF-IL6 ATF Cyclin D Cyclin D Cyclin A,E CDK1 Specificgeneproducts Cyclin B Nucleus

4. Variouslevels of interventionI ATP Proteolysis D C B A F E Substrate Protein G DNA RNA P

5. Variouslevels of interventionII • 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 surfacereceptorswithmonoclonalantibodies

7. Selectedkinaseinhibitorsinclinicaldevelopment

8. Calcineurin and rapamycin CyPA FKBP12 FKBP12 CsA R FK506 B FRB mTOR Calcineurin A CaM T-cellactivation Cation stress Translation Cell-cycle

9. Rapamycin a b g IL2 IL2R FKBP12 R PHASI p70S6K PI3K ? mTOR AKT Apoptosis P27kip1 Bcl-2 G1 S phase

10. Toll-like receptor inhibitors LPS Polymixin B LBP TLR2 TLR4 MD2 OxPAPC CD14 dsRNA CLI095 TBK1 IKKe Chloroquine MyD88 MyD88 TLR9 TLR7 TLR3 RIG-1 MDA-5 JAK2 AG490 LY294002 IPS1 PI3K Wortmannin BX795 mTOR Rapamycin MyD88 TRIF PepinhMYD PepinhTRIF PKA TAK1 PKR H-89 2-Aminopurine PD98059 Bay11-7082 MKKs lkB p50 U0126 Celastrol p65 p38 JNK SB203580 SP600125

11. ERB signalingintervention Anti-ErbBantibody (e. g. Herceptin) ErbBdimer Unfolded, inactive ErbBdimer Ligand Tyrosinekinaseinhibitors (e. g. tryphostins) Hsp90 inhibitors (e. g. geldanamycin) Phosphoproteins and downstreamsignallingevents Hsp90 scFvs Triplex-formingoligos, antisenseoligos Nucleus ImmatureErbB Transcription Translation ErbBgene ER/Golgi Ribozymes

12. Proteosomeinhibitors-Bortezomib Cytokines activate cell-surface receptors O OH ↓Cytokines H N N B OH N Activation of NF-kB bydegradation of IkB H O N P105 precursor processed p105 Bortezomib ↓ Anti-apoptotic factors p50 lkB p65 Proteasome ↓ Inflammatory molecules lkB p65 p50 p50 p50 NF-kBactivates transcription NF-kB Degraded IκB p65 p65 Nucleus ActivatedNF-kBtranslocates tothenucleus ↓Celladhesion molecules

13. Apoptosissignalingintervention TRAIL DR4/DR5 Chemotherapy Bcl-2 Bcl-xL HDAC inhibitors FADD Bcl-2 inhibitors Caspase-8 c-FLIP Pro-caspase-3 tBid Bid Bax Bak Caspase-9 Caspase-3 Cytc lkB P NF-kB lkB p53 Smac/Diablo Proteasome IAPs IAP inhibitors P APOPTOSIS Proteasome inhibitors Bcl-2 Bcl-XL Bfl-1/A1 c-FLIP DcR1 c-IAP1 c-IAP2 XIAP NF-kB DNA damage

14. HSP-90 inhibitors Mature complex HSP90 HSP90 Intermediate complex HSP90 HSP90 ADP ATP CDC37 p23 Immunophilin HARC AH1 CLIENT HOP CLIENT HSP40 HSP70 HSP90 HSP90 Geldanamycin binds to the ATP-binding site of HSP90 Early complex Proteasome + CLIENT HSP40 UB UB UB CLIENT UB UB HSP70 Ubiquitinligase CHIP Ubiquitinproteasome-dependent degradation