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. 1999 Dec;104(11):1503-6.
doi: 10.1172/JCI8888.

Choosing anticancer drug targets in the postgenomic era

W G Kaelin Jr  1
Affiliations

Choosing anticancer drug targets in the postgenomic era

W G Kaelin Jr. J Clin Invest. 1999 Dec.
No abstract available

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Figures

Figure 1
Figure 1
Simplified views of the pRB and p53 pathways. The cdk4 and cdk6 kinases are positively regulated by G1 cyclins such as the D-type cyclins and negatively regulated by cdk inhibitors such as p16/INK4A. Cdk4 and Cdk6 phosphorylate, and thus inhibit, the retinoblastoma protein (pRB). pRB forms complexes with members of the E2F transcription factor family. These complexes repress transcription from E2F-responsive promoters. p53 is a sequence-specific DNA-binding protein that transcriptionally activates target genes such as p21/WAF1 and BAX. HDM2 silences the p53 transcriptional activation domain and targets p53 for degradation. ARF antagonizes HDM2. As indicated by the dashed lines, these apparently linear pathways are subject to cross-talk, which links them into a more complex regulatory network.
Figure 2
Figure 2
Basis for therapeutic window. A therapeutic window can either be target-driven or context-driven. In target-driven drug design (a), the target molecule is unique to the diseased tissue. The context-driven strategy (b), on the other hand, is directed at a target that is present in both normal and diseased tissue. This alternative approach takes advantage of mutations or other physiological changes (hatched marks) that occur during tumorigenesis and that alter the cell’s or tissue’s requirement for the target protein. Such changes may include quantitative effects, as when a tumor cell becomes dependent on high expression of the target protein, or they may be qualitative, if the target protein takes on novel functions that sustain the growth of the diseased tissue.
See this image and copyright information in PMC

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