In vitro, CCF642 inhibits PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggests a novel covalent binding mode in active-site CGHCK motifs. CCF642 causes acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release.
In vivo
CCF642 displays potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolongs the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib.
