Compartmentalized cancer drug discovery targeting mitochondrial Hsp90 chaperones - PubMed (original) (raw)

‘Target-centric’ cancer drug discovery (left panel) involves the selection of a target gene, and the generation of inhibitors by high throughput screening, and lead optimization. These agents may inhibit the target, and cause indirect activation of mitochondrial cell death,

in vivo

, but anticancer activity is often reduced by pathway redundancy and compensatory prosurvival signals. Conversely, combinatorial engineering of pathway inhibitors, for instance 17-AAG, to target a subcellular cancer network, i.e. mitochondria (right panel), generates antagonists that directly induce organelle collapse, and enhanced anticancer activity, bypassing compensatory survival mechanisms. ΔΨm, mitochondrial membrane potential, PTP, permeability transition pore; cyt c, cytochrome c, CypD, cyclophilin D.