Model Organisms in Drug Discovery

A CASE STUDY FOR ALZHEIMER’S DISEASE DRUG DISCOVERY 169
Figure 6.5 Compound BMS AG6B does not induce sterility in sel-12 mutants. (A)
Control (DMSO)-treated sel-12(ep6). (B) A sel-12(ep6) hermaphrodite treated with
1.6 mM BMS AG6B. Animals are fertile but have dead eggs
Table 6.3 Summary of phenotypes of BMS AG6B-treated C. elegans presenilin mutants
Phenotypes
Genotype Drug Egl-d Dead embryos Sterile
Wild type No No No
Wild type + Yes Yes No
sel-12 Yes No No
sel-12 + Yes Yes No
hop-1 No No Yes (0.5%)
hop-1 + N/A N/A Yes (100%)
hop-1;sel-12 N/A N/A Yes
of presenilin, suggesting that they contain the active site of the protease (Esler
et al., 2000; Li et al., 2000). These data are also consistent with reports of worm
and fly phenotypes induced by another gamma-secretase inhibitor, compound
E (Francis et al., 2002). The genetic data here also support the hypothesis that
Notch processing is due to the same activity as APP processing, and this was