CCF642

CCF642 is a **novel small molecule inhibitor** of protein disulfide isomerase (PDI), specifically targeting the PDI isoenzymes PDIA1, PDIA3, and PDIA4. The compound works through **covalent modification** of the catalytic site lysine residue in active-site CGHCK motifs, leading to irreversible PDI inactivation. This mechanism induces **acute endoplasmic reticulum (ER) stress** that overwhelms the capacity of cancer cells to maintain proteostasis, ultimately triggering apoptosis through calcium release and activation of pro-apoptotic pathways including PARP and caspase 3 cleavage. CCF642 demonstrated submicromolar IC50 values across 10 multiple myeloma cell lines and showed **potent in vivo efficacy** in syngeneic mouse models of myeloma, with effects comparable to bortezomib. The compound exhibits **bone marrow-sparing properties** and maintains therapeutic efficacy against bortezomib-resistant myeloma cells. CCF642 was discovered through a mechanistically unbiased screening of a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay. While CCF642 showed promising preclinical results, it has **poor solubility and suboptimal selectivity**, which led to the development of improved analogues like CCF642-34 with better drug-like properties for potential clinical translation.