CB-5300

CB-5300 is a second-generation small molecule inhibitor of the AAA+ ATPase **p97** (also known as **Valosin-Containing Protein** or **VCP**), developed by **Cleave Therapeutics**. It was specifically designed to improve upon the safety profile of the first-generation inhibitor, CB-5083, which encountered clinical setbacks due to off-target ocular toxicity caused by the inhibition of phosphodiesterase 6 (PDE6). p97 is a central regulator of protein homeostasis, facilitating the degradation of misfolded proteins through the ubiquitin-proteasome system and the endoplasmic reticulum-associated degradation (ERAD) pathway. By selectively inhibiting p97, CB-5300 induces significant proteotoxic stress and triggers the unfolded protein response (UPR), ultimately leading to apoptosis in cancer cells. The drug was primarily investigated for its potential in treating multiple myeloma and various solid tumors that are highly dependent on protein quality control mechanisms.