Figure 3. The use of the Clinical Compound Library (CCL) to screen for inhibitors of hubs of human disease networks.

(a) Depiction of toxins as well as their pathways that induce caspase-mediated cell death. These toxins enter into host cytoplasm either from acidified endosomes or endoplasmic reticulum. Broad-spectrum anti-toxin drugs are screened to identify inhibitors of host caspases. (b) Overall approach scheme: CCL is screened by a multiplex approach that incorporates biochemical FRET and cell survival assays looking for drugs capable of simultaneously inhibiting host caspases-3/6/7 and reducing cytotoxicities of three bacterial toxins. The output of this approach is the discovery of broad-spectrum and host-oriented drug, Bithionol. (c) Schematic diagram of cellular screens to identify drugs that reduce cellular lethality induced by diphtheria toxin, Pseudomonas aeruginosa exotoxin A, and cholera toxin. Numbers are the distribution of inhibitors obtained in all screens. (d) Schematic diagram of parallel FRET screens to identify drugs that inhibit proteolytic reaction of caspases-3, -6, and -7.