??DNA??????????(??S?)

1
2. ????
??DNA??????????(??S?) ???????????purine,
pyrimidine, folate ????????????,???????? ???? ???
???????????(???????),??????? ??????????????,??????
??????,??????,lethal synthesis
?????(??????S?DNA???????G1/S???)
??????????,?Na2SO3, ????????,????,????
????Fluorouracil 5?H??????F?? ??????FUdRP?Thymidyl
ate synthetase??? ????????,?????
???
2
Tegafur, 5-FU??
Capecitabine, ???5-FU
Cytarabine???? ??AML ?????????? ?????????? t1/2?,
???????????????????????
Gemcitabine, ??????????NSCLC???????? ?????,???????
?????????????,??DNA??,???????
3
?????
????????DNA????,????????????????
MPRP
Mercaptopurine??? 6-MP????????????????OH?SH
4
????tioguanine ???9-(1-ribosyl-5-phosphate), ??
???????,???????DNA
Fludarabine ??CLL ???????
Cladribine ?????????
5
Dihydrofolate reductase inhibitors (?????)
????,?????,????????????
Folic acid
dihydrofolic acid
MTX?????,????,??????????????
Methotrexate ???? ?DHFR???104X
6
MTX????N1,???C2-NH2 (PDB1U72) ???(N1)????????,N
1/C2-NH2????DHFR E30/T136??? C10-NH2?I7/Y121/V115?
??? Glu?a-COOH?R70??????????? ?????????????F31/F3
4/I60 ??Pteridine?????A9/F34/L22 ???? (PDB
4M6K) ???????????????MTX N1???,N3/N11?E30??? ?????
? Pymol Demo
7
Raltitrexed thymidylate synthase inhibitor
Hydroxycarbamide Ribonucleotide reductase
inhibitor
pentostatin Adenosine deaminase inhibitor IV
????????
8
3. ??????
??????4??? G2????,??????(????,??????????????) ???
???????????,??????????????????????, ??????
????Colchicine ???? ???????????????? ??????,??????
????????????,??????????,????? ??????
R R1 R2
???binblastine Me OMe COMe
????Vincristine CHO OMe COMe
???/????????(Eli Lily),?????????????? ????????????
9
?????????
????Vinorelbine, ???? ???? ????lt????
????vindesine ????,????????????
??????,???????????,?????????
????25nm????????,?????????????????,?????a,b???
10
????
1964NCI?????????? 1966??taxol 1971Structure 199
0s?? ????(?????)??? ????????????,??????,???????
,????????????,???????????? ???/????????????NSCLC??
???? ??????baccatin???????,P-???????????????????
???
Paclitaxel/taxol ???
docetaxel
11
4. ??????
??????????/??????????????????????????????,????????
?????????????????????????,?????????????????,??????
?/??????? ???,????

1. Kinase inhibitors
2. Ras???????
3. ???????
4. Ub-Proteasome???
5. mTOR????

12
?????

• ?????????????????????????????????????????
• Serine/threonine-specific kinases
• Tyrosine-specific kinases
• Mixed function kinases
• Receptor kinases ?????????????????????
  erbB(HER),Platelet-derived growth factor
  receptor vascular endothelial
  growth factor receptor, e.g., IGF-1R, KIT, mutant
  FLt-3??
• Nonreceptor kinases ????/???,????????????????,???
  ????????????????,eg. ABL, JAK, FAK, SRC

????????????????????????????,?????????-??????????
????????
serine
threonine
tyrosine

• ??
• Receptor tyrosine kinase?????????????,?????RTK,???
  ?/??,????
• ???????????????

13

• ????????
• ???????????????,e.g., TGF-b??????????
• ???????????,??????
• ?????/???????,
• ????????????
• ??????????????????,??????????????????
• ??????e.g., BCR-ABL????CML??,???15-30de ALL,
  100CML
• ????OverexpressionEGFR, ErbB2/Her2/neu, ErbB-3,
  ErbB-4?Breast Cancer???? PDGFR???????????????????
  ??????????????????SRC??_at_???
• ????????????ATP????,??????

14
Imatinib, Gleevec
????????,??????? ?????????BCR-ABL??????????????CML
Druker??imatinib??CML,90??????????????????
????,???? ???????????? ??????ABL, PDGFR,
c-Kit??(??GISTs)
Enjoy the video from Brain Druker
at http//bionmr.ustc.edu.cn/courses/druker_imatin
ib.wmv
15
EGFR inhibitors
Gefitinib, Iressa (AstraZeneca) clogP4.02
clogSw-22
Phase II and Phase III results are not
consistent? personalized medicine (mutations
common in Asians, women, and non-smokers)????????,
?????????
TGF-a/EGF???????EGFR ? homodimer/heterodimer?Tyros
ine Kinase ?cascade Overexpression of EGFR in
solid tumors ??????????? ???EGFR???????????/??
16
???? Erlotinib, Tarceva
clogP3.92 clogSw-4.81 Pfizer??,Roche/OST/Genent
ech?? ??NSCLC, ??(???) ????,EGFR??????????,??? EGF
R????? Personalized medicine
Other targets VEGF(semaxanib), PDGFR,IGF-1R,
MET, SRC, Ras, AKT, STAT,PKB, etc.
17
Ras signal transduction inhibitors
30 cancers start from Ras oncogene
mutation??90Ras ?? 50???,90???Ras?????,
39???Ras?? Mutant Ras patients survival median
2.1yr,wt-Ras 4yr
Ras (21kDa) belongs to Rat-Adeno-Sarcoma
superfamily
????Ras???????????????RTK???RTK???Grb2??????????r
ecruit Sos?Ras-GDP(inactive) to Ras-GTP
Ras???GFR???????,Ras???????Ras C-terminal CaaX
(aaliphatic, X SMAQ) ????,??aaX,S-Farnesyl-Cys?
COOH???,?????
Ras????GTP???,???Ras-GTP?,??????????,????????????
18
FTase Inhibitors
Farnesyl pyrophosphate FPP
CaaX????F/CVFM ????,???? FPP?????????????,???
Tipifarnib(Janssen?JJ,Phase III) ???????????????
??,??????????? PI3K/AKT2??? ???Ras???
Lonafarnib Indication NSCLC
19
???????
Cyclin-dependent kinase, CDK4/6?????????????,?G1??
????????pRb, ??pRb?????????D1???Ras????upregulated
Flavopiridol ??rohitukine?????? Phase II??
Olomoucine
roscovitine Cyclocel??,phase II
????????ATP???? Cheng-Prusoff??
Alsterpaullone ?CDK1, GSK-3, CDK5
?????ATP??515mM ??IC50???????
20
Ubiquitin-proteasome inhibitor
?????????????????????????????? ??????????????????
??????? ????????????????????????????
Bortezomib, Valcade (Millennium
Pharm) ????????? Ki????????????????? ????????
More targets NF-kB??????????????,?????????IkB????
?NF-kB??
21
mTOR????
PI3K-mTOR???gt70?????
??FKBP12??,??mTOR
??? R ??
Rapamycin H Wyeth????,????
AP23573 -PO(CH3)2 BC, GIST
everolimus CH2CH2OH Metastatic BC, PII
temsirolimus COC(CH3)(CH2OH)2 PIII, combo
????
??
???? ???? ??
????
Biomarker pS6, p4E-BP1, pS6K ??
22
Epigenetic protein families a new frontier for
drug discovery
Nature Reviews Drug Discovery, 2012
23
Personalized Medicine
Biomarker ?????,????????/?? ??????????,??????????
??? ??????????,????????? Genomics/proteomics??
Cancer Genes
Breast Cancer BRCA1/2, ATM, HER2
Burkitts lymphoma c-Myc
Colorectal Cancer MLH1,MSH2/6, KRAS mutation
Lung Cancer EGRF, HER2/3/4
CML BRC-ABL
Melanoma CDKN2, BCL-2, BRAF V600E mutation
endothelioma VEGFR, VEGFR2
Others P53, PKA, VEGFR, VEGFR2, PDGF, PDGFR
More reading R. Schilsky, Personalized medicine
in oncology the future is now Nature Reviews
Drug Discovery, 2010