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CCCCNCC
H 2 H 2 H 2 C H (C H 3)2
H 2 H 2
O C H 3 O C H 3
CH3
wenku.baidu.com
CH3
Rapamycin
Verapamil
mechanism of action of Pglycoprotein
Ultimate Goal:
To use molecular analysis of human cancers to predict response to specific therapy
To use this information to develop novel drugs to treat cancer
Increased efflux
Drug Resistance in Cancer
May affect multiple simultaneously: known resistance (MDR)
drugs used as multidrug
Affects all classes of drugs, including newly designed targetted drugs
ABC linker Walker B D-
loop Y GNSGCGKST LSGGQKQRIAIA ILLLD EA TSALD
Structural Organization of an ABC Transporter
Transmembrane Domain
R
\/\/\ ATP-Binding Domain
Substrates and Reversing Agents of Pgp
N H H3 C OOC
OH N
C H 2C H 3
N H
H3 C O
N HO
CH3
C H 2C H 3
C
O
C O
OO CH
C
3
H
3
Vinblastine
O
OH
C H OC H3 OH
H
O
OCH3 O
OH
H
H H 3C H
ABC transporters: Domain organization
ABCB1
TM Domain
TM Domain
ATP binding
ATP binding
ABCC1
ABC G2
Hypothetical Model of Human P-glycoprote
100
OUT MEMBRANE
P-GLYCOPROTEIN AND DRUG TRANSPORT 膜蛋白和药物转运
Estimated New Cancer Cases & Deaths, 2005
**Vast majority of deaths due to chemotherapy resistance
CA Cancer J Clin, 2005
D
D
e.g.n, ucleoside analogs
Endocytosis
D D
e.g., immunotoxins
Mechanisms of Resistance
Overexpressed Fewer Functional Defective endocytosis ABC Transporters UptakeTransporte
Just as oncogene targets have been catalogued, we need to enumerate all mechanisms of drug resistance in cancer to solve this problem and circumvent resistance
IN
200
ATP SITE 300
A
B
700
P
400
C
800
P
900
P 600
P
1 500
POINT MUTATIONS ( ), PHOTOAFFINITY LABELED REGIONS ( ), AND PHOSPHORYLATION SITES ( P )
1000
ATP SITE
A
1200 B
OH
O H
NH2
H
Daunorubicin
H3C O
OCH3
L -Pro
Sa r L-M eva l
L -Pro
Sa r L-M eva l
H3C O
D -V al
O
L- T hr
OC
D -V al
O
L-T C O hr
H3C O O
N H CO CH 3
N
NH2
O
O
Colchicine
CH3
CH3
rs
DIFFUSION
D DD
D
D
D
D D
D
D
D
D
(ABCB1) D
D D
Pgp
D D
D
D
(ABCG2)
D MXR
DD
GS D
D
MRPs
ABCC1-C4
DD
ATP-BINDING CASSETTE
(N-terminal NBD of human Pgp)
390 427A
C B 556
620
Walker A
resistance to anticancer drugs
Decreased uptake
Reduced apoptosis Altered cell cycle checkpoints Increased metabolism of drugs Increased or altered targets Increased repair of damage Compartmentalization
Actinomycin D
O
H3C H3C
C O
O CH3 OH
O
OO
H C NH C C C O
CH3
H
CH3
O
HO O
O C CH3
CH2
O
Taxol
HO
H3C O
O HO H 3C
H 3C O
N O
O
O
OCH3
CH3
O
OH
H 3C
O H3C O
H 3C
H 3C O H 3C O
C N
C H 3
C 1100
1280
Structure of E.coli BtuCD, a vitamin B12 transporter.
Locher et al. Science. 2002
20 transmembrane helices
X-ray structure 3.2 A
ATP binding domains
To learn more about cellular pharmacology and pharmacokinetics of drugs
How Drugs Get Into Cells
Diffusion
D D
D
e.g.v, inblastine, dox o ru bicin
Transport
