CCF-642 is an inhibitor of protein disulfide isomerase (PDI).1 It inhibits the reducing capacity of PDI when used at a concentration of 1 ?M. It inhibits proliferation in ten multiple myeloma cell lines with IC50 values of less than 1 ?M. It is cytotoxic to primary cells isolated from patients with refractory myeloma who developed secondary plasma cell leukemia (IC50 = <1 ?M) but not to normal bone marrow mononuclear (NLBM) cells up to a concentration of 6.75 ?M. CCF-642 (3 ?M) also induces acute endoplasmic reticulum (ER) stress, increasing ERK phosphorylation and dimerization of IRE1-α, indicating an increase in the amount of misfolded ER proteins. It increases calcium accumulation and cleaved caspase-3 in MM1.S cells and induces apoptosis. CCF-642 increases survival in a 5TGM1 mouse syngeneic model of myeloma when administered at a dose of 10 mg/kg three times per week.
1.Vatolin, S., Phillips, J.G., Jha, B.K., et al.Novel protein disulfide isomerase inhibitor with anticancer activity in multiple myelomaCancer Res.76(11)3340-3350(2016)