CCF642-34

CCF642-34 is a first-in-class, orally bioavailable, irreversible small molecule inhibitor of protein disulfide isomerase A1 (PDIA1). Developed by researchers at the Cleveland Clinic, it is a lead candidate optimized from the hit compound CCF642. CCF642-34 targets the active motif (CGHCK) of PDIA1, an ER-resident chaperone essential for the folding of secretory proteins like immunoglobulins. By inhibiting PDIA1, the drug induces unresolvable endoplasmic reticulum (ER) stress and subsequent programmed cell death (apoptosis) in clonal plasma cells. It is being investigated for the treatment of plasma cell dyscrasias, including multiple myeloma and primary light chain amyloidosis, where it has demonstrated efficacy in restricting clonal plasma cell evolution in vivo while maintaining a favorable therapeutic index.