VCP Inhibitors

VCP inhibitors belong to a distinct and significant class of chemical compounds that target the valosin-containing protein (VCP), also known as p97. VCP is an essential enzyme involved in a variety of cellular processes, primarily functioning as a ubiquitin-dependent segregase in protein quality control pathways. VCP is instrumental in facilitating the extraction of ubiquitinated misfolded proteins from the endoplasmic reticulum, a crucial step in maintaining cellular protein homeostasis. In this context, VCP acts as a central player in the ubiquitin-proteasome system, participating in the proteolytic degradation of aberrant proteins. The inhibition of VCP disrupts this vital mechanism, leading to the accumulation of misfolded proteins and endoplasmic reticulum stress, which triggers cellular responses such as the unfolded protein response and autophagy. The design of VCP inhibitors typically centers on disrupting its ATPase activity, as VCP requires ATP hydrolysis to power its segregase function. Small molecules that inhibit VCP bind to its ATPase domain, impeding its ability to hydrolyze ATP and consequently hindering its role in protein extraction and degradation. Various classes of VCP inhibitors have been developed, each characterized by distinct chemical structures and binding mechanisms. Researchers have extensively investigated these inhibitors as valuable tools for probing cellular protein quality control pathways and deciphering the role of VCP in various physiological and pathological contexts. Furthermore, the study of VCP inhibitors has contributed to a deeper understanding of cellular proteostasis and the mechanisms underlying protein misfolding diseases. Overall, the development and exploration of VCP inhibitors have provided significant insights into the intricate landscape of cellular protein quality control mechanisms, shedding light on avenues for modulating these processes in various cellular and disease contexts.