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本帖最后由 细胞海洋 于 2010-6-19 19:27 编辑
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" x7 h7 ^7 l+ q1 L- V* `+ GPreface
: n) \3 E0 N8 h& pTarget discovery is a field that has existed for several years but is so vibrant
2 @# E& H5 H& O/ ytoday because of the recent progress in our understanding of the molecular
) \3 @ j/ p: h5 y Tmechanisms of many human diseases and the technical advances in target; F5 W8 S' ]6 x; W ~: v
identification and validation. More sophisticated gene profiling technologies,$ h3 B' H/ s q1 v u. G* m, E
such as DNA microarrays and serial analysis of gene expression, permit rapid3 I5 N% ?+ s& ~7 O# |6 l4 z: q
identification of lead targets. Moreover, analysis of gene networks in living
8 w \ C6 m& G- {2 e, ^; C) \3 U; Korganisms allows the identification of target genes that operate in defined
# v) k( I( X) W7 D; Sphysiological pathways. With the sequencing of several genomes completed" S. ^$ l3 M7 |& V8 q" F
and the rapidly growing gene expression databases, there is now greater
+ [* v% t \( P0 A6 _* _! l: U+ a! Qimpetus than ever before for in silico discovery of therapeutic targets. Also,
. T/ W% [; i+ p" Y1 |5 F) G' erecent advances in genetic technologies have increased our ability to generate
5 c( ~$ h4 l8 K( y+ w& ~mouse models for human diseases. The implications of these genetically+ A6 B' F5 K* |6 }
modified animals in drug development are several, including identification of( f7 L3 A: n! k
new drug targets, predicting efficacy, and uncovering possible side effects.
# }0 P. Q1 x( p3 t0 _9 C% \Together, these recent technical advances should allow researchers to make, W- U1 x; V3 u4 W% m+ w$ y: Z
the most informed choice early and advance the chosen targets toward clinical9 E6 @2 ~# i7 O, t( E4 L6 P3 X, n
studies.2 W6 S# p/ i+ h# \4 n' r6 }
Regarding cancers, any difference between a cancer and a normal cell could
; ^: C5 { }% i2 K/ I# Jpotentially be exploited as a therapeutic target. The hope is that drugs targeting
; o `8 ?# y" l2 r# p+ P0 cspecific constituents or pathways in cancer cells will provide more effective
! Q: P) s% P f @/ Q% s r/ |therapy, either alone or in combination with other currently used anticancer
, e0 F4 i- s/ D+ D0 P4 [* zdrugs. In addition to drug targets, identifying new target antigens remains as
- m6 z/ K$ u6 ^( S1 q3 ]much of a challenge as improving tumor vaccines already in the clinic. New
# [( G$ Y! j7 gtechniques such as SEREX, phage display, proteomics, and reverse immunology
* ]. ^2 N- r% _6 z" thave not only yielded a significant number of new tumor antigens, but they have5 f K. e, }! }$ J- s' C
influenced our understanding of the interaction between the immune system and- u6 T" b. L1 r4 d; E( |
tumor cells. New adjuvants to improve vaccine potency are also being
# g1 u4 W+ v/ g; |7 G, [7 P+ q/ _3 u! wdiscovered.7 F; i' W+ J( Y8 Y
Validating potential drug targets is one of the most critical steps in drug! a2 u9 C" N. G
discovery. At present, the currently available target identification technologies" E' r: S( f; x) o' w" d0 Q
appear to yield too many targets. Therefore, programs need to focus on defining7 ^+ ^; P s% J7 f2 l1 B+ W
the targets that are specific and “druggable” with small inhibitors. While true7 G- y! S7 |0 }" [5 m, S& r d
target validation comes only when a selective inhibitor for the chosen target is
0 j9 J5 o0 J% r7 C. [. Jtested in patients and exhibits efficacy in the appropriate human disease, the6 Y0 I$ Q' o! v8 x3 X
appropriate cell culture and animal studies prior to the trial are not only required
7 ^; b* M% e; Z5 s. F+ l- pbut should provide crucial information regarding the validity of the chosen tar
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发表于 2010-6-19 19:01
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