Date post: | 26-Mar-2015 |
Category: |
Documents |
Upload: | elizabeth-rice |
View: | 218 times |
Download: | 0 times |
UNIVERSITA’ DEGLI STUDI DI PALERMO
FACOLTA’ DI FARMACIA
Design, synthesis and biological evaluation of new inhibitors of
carcinogenic processes
DIPARTIMENTO FARMACOCHIMICO TOSSICOLOGICO E BIOLOGICO
Dott. Ilenia Abbate
2
Cancer cells are less sensitive to the therapy and repopulate the tumor, facilitating tumor progression
Migratory growth factorMigratory growth factor
PROTO-ONCOGENEPROTO-ONCOGENE
STAT3c-MYC
growth factor-growth factor-induced induced
mitogenesismitogenesis
RasERK
MERKCyclin/cdks
promotes G1/S phasepromotes G1/S phase
PI 3 kinaseAkt
survival survival
SIGNAL-TRANSDUCTION PATHWAYS CORRELATED TO TUMOR PROGRESSION
Without fuctional HSP90, these proteins undergo proteasome-mediated degradation, leading to cell cycle arrest and apoptosis.
4
HSP90 chaperone stabilizes
oncoproteins
Inhibiting HSP90 degradesoncoproteins, stopping
tumor growth
5
ability to evade apoptosis ability to be self-sufficient for growth ability to invade surrounding tissue and to metastasize to distant sites
Multiple HSP90 client proteins mediate acquisition and maintenance of the six properties necessary for transformation of a normal cell into a cancer cell:
ability to undergo limitless replicationability to promote neoangiogenesis ability not to respond to antigrowth signals.
•Folding
•Biological fuction
•Stabilization/Degradation
•Activation
•Folding
•Biological fuction
•Stabilization/Degradation
•Activation
CLIENTS
PROTEINS
•Protein kinases (Her-2/ErbB2 e Akt)•Cdk4/ciclin D complex•c-Raf-1•HIF-1α•p53•Steroid hormone receptors
HSP90 stress condition: heat, irradiation, ROS (reactive oxygen radicals), toxins, lack of
nutrients, hypoxia, bacterial and viral infections.
-C-terminal domain : 10kDa, omodimerization and co-chaperones recruitment super-chaperone complex;
-middle region: 35kDa, binding site for client proteins and ATPase activity;
-N-terminal domain: 25kDa, binding site for ATP/ADP and inhibitors, such as geldanamycin and radicicol.
OH
HO
Cl
O
O
O
O
Me
O
O
NH
O
Me
MeO
OCONH2
MeMeO
Me
Me
OH
R
Geldanamicina R= OMe17 DMAD R= NHCH2CH2NMe2
17 AAG R= NHCH=CH2
N
N
NH2
RX
Y
OMe
OMeOMe
O
O
OO
HO
OH
O
O
HO
OH
OH
Derrubone
Apigenina
PU3 X=Y=H R= C4H9
PU24FCl X=F Y=Cl R= (CH2)3C CH
Radicicolo
N N
H
R4OH
HOR1
R2
R3
G3129 Et - O- CH2- O- COOH
CCT018159 Et - O- (CH2)2- O- Me
VER- 49009 Cl OMe H CONHEt
R1 R2 R3 R4
BINDING PROTEIN…
geldanamycingeldanamycin
HYDROPHOBIC INTERACTION:Leu48, Lys58,
Met98, Thr109, Val136, Phe138, Val150, Val186
H-BOND ACCEPTORS/DONORS: Asp51, Asp54, Lys58, Asp93,
Gly97, Lys112, Phe139,Thr184
N S
NN
NN
O
N
NH
NH
O
PURINES12
PYRAZOLES28
SULFONAMIDES9
HSP90 INHIBITORS
PU1 PU2 PI1 PI2 SU1 SU2
HYPO1 HYPO2
ZINC DATABASE5,627,809 compounds
Lipinsky’s Rule
Molecular DockingHTVS Glide level
MolecolareDockingSP Glide level
MATCHING HITS
MOLECULAR DOCKING/
PHARMACOPHORE APPROACH
MOLECULAR DOCKING/
PHARMACOPHORE APPROACH
N
N
NHAr
NHO2S N
N
RR
O
Ar
N
N
NH
SO2 R
Ar
O
N
CN
NH2
12
3 4
N N
O
NHSO2Me
R1 R2
R3
9a- k
N
NH2NC
NHSO2MeR1
R2
R3
10a- k
X S
NN
NN
O
R'
R
11
N N
O
NHSO2Me
R1 R2
R3
9a- k
N
NH2NC
NHSO2MeR1
R2
R3
10a- k
O
NHO2S
6
O
NH2
CH3SO2Cl
Pyridine
5
R1
R2
R3
O
NaOH/H2O/EtOH
O
R1
R2
R3
NHO2S
7a- k
8a- k
N2H4/H2O
AcOH
NCCH2CNNH4Aca: R1=Cl, R2=R3=H
b: R1=R2=H, R3=NMe2 c: R1=R3=H, R2=F d: R1=OCH3, R2=R3=H e: R1=H, R2=R3=OCH3 f: R1=R2=H, R3=OCH3 g: R1=R2=H, R3=OH h: R1=OH, R2=OCH3, R3=H i: R1=R3=H, R2=OCH3
j: R1=R2=H, R3=NEt2 k: R1=Br, R2=R3=H
R=CN, PhX= CH, N
- CH2CH2CH2COOH - CH2CH2CH2COOCH2CH3
- CH2COOCH2CH3
- CH2CH2CH2Cl - CH2CH2CH2N(CH2CH2CH3)2
- CH2CH2CH2 N N CH3- CH2CH2CH2 N
- CH2CH2CH2CONHCH2COOCH2CH3- CH2CONHCH2COOCH2CH3
- CH2CH2CH2CONHCH2COOH - CH2CONHCH2COOH
- CH2COOH
- CH2CH2CH2CONHCH2CH2
NH
N - CH2CONHCH2CH2NH
N
- CH2CH2CH2CONHCHCH2
NH
NCOOCH3
- CH2CONHCHCH2
NH
NCOOCH3
- CH2CONHCH2CONHCH2CH2
NH
N
- CH2CONHCH2CONHCHCH2NH
NCOOCH3
- CH2CH2CH2CONHCH2CONHCH2CH2
NH
N
- CH2CH2CH2CONHCH2CONHCHCH2NH
NCOOCH3
- C
CHCOOCH2CH3
CH2COOCH2CH3 - C
CHCOOH
CH2COOH
X S
NN
NN
O
H
R
15
12
X
CN
F
HSCH2COOEt
NaH DMSO X
CN
SO
OX S
O
O
NH2
X S
O
O
NN
N
R
N
13
14
EtONa/EtOH
X S
NN
NN
O
R'
R
11
X S
NN
N
N
O
R
R'
16
NATIONAL CANCER INSTITUTE, Bethesda
DEVELOPMENTAL THERAPEUTIC PROGRAM
Leukemia
Non Small Cell Lung Cancer
Colon Cancer
SNC Cancer
Melanoma
Ovarian cancer
Renal Cancer
Prostate Cancer
Sub Panels of Human Tumor Cell
Lines
Breast Cancer
15
S
N
N
O
NN
Ph
HN
O
NH
N
K-562:pGI50=7.64
LEUKEMIACNS CANCER
SF-539:pGI50=7.69
RENAL CANCER
SN-12C:pGI50=7.96
16 side chain O
16
N
NH2NC
NHSO2MeN
10 b
60 cell lines single dose of 10 uM
TUMOR
• GIST• NSCLC• PROSTATE (PTEN-/-)• BREAST (HER2 +)• MELANOMA
HSP90 CLIENT PROTEIN
• c-Kit• EGFR / C-met• AR / p-Akt• HER2 / ER• b-Raf (V800E)
DIPARTIMENTO FARMACOCHIMICO, TOSSICOLOGICO E BIOLOGICO
• Prof. Anna Maria Almerico• Prof. Antonino Lauria• Prof. Gaetano Dattolo
• Prof. Maria A. Livrea• Prof. Luisa Tesoriere• Dott. Carla Gentile