CP4.2

CP4.2 is a small molecule pharmacological chaperone designed to stabilize the Von Hippel-Lindau protein (pVHL). It is a derivative of the compound CP4 and was developed to rescue pVHL missense mutations associated with Von Hippel-Lindau disease (VHLD) and clear cell renal cell carcinoma (ccRCC). Unlike traditional inhibitors that disrupt the VHL:HIF interaction, CP4.2 binds to a cryptic pocket near the Asp197 residue of pVHL. This binding stabilizes the protein's tertiary structure, potentially restoring its canonical function in the VCB E3 ubiquitin ligase complex (mediating the degradation of hydroxylated HIF-α) as well as its non-canonical functions, such as the control of mitotic integrity and spindle checkpoint activity. By correcting the protein folding defects caused by germline or somatic mutations, CP4.2 represents a novel therapeutic approach for treating VHLD-associated tumors and spontaneous ccRCC.