Valosin-containing protein (VCP) (VCP)

Valosin-containing protein (VCP), commonly referred to as p97, is a highly conserved member of the AAA+ (ATPases Associated with diverse cellular Activities) family that serves as a central hub in cellular protein homeostasis (UniProt P55072; Tang & Xia, 2016). It functions as a hexameric molecular machine that utilizes the energy from ATP hydrolysis to unfold and extract ubiquitinated proteins from various cellular structures, such as the endoplasmic reticulum or chromatin, for subsequent degradation by the proteasome (Anderson et al., 2015). The protein architecture includes an N-terminal domain for cofactor binding and two tandem ATPase domains, D1 and D2; the D2 domain is the primary site of ATP hydrolysis and the principal target for pharmacological inhibition (Huryn et al., 2020). In oncology, p97 is frequently overexpressed to manage the high proteotoxic stress of malignant cells, and its inhibition triggers the unfolded protein response (UPR) and apoptosis (Anderson et al., 2015). Mutations in VCP are also genetically linked to neurodegenerative conditions, including inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD) (UniProt P55072). While first-generation D2-specific inhibitors like CB-5083 showed potent anti-tumor activity, clinical development was hampered by off-target retinal toxicity, leading to the pursuit of more selective agents like CB-5339 (Huryn et al., 2020).

Other names

p97Transitional endoplasmic reticulum ATPaseTER ATPaseCDC48p97 D2 ATPase domain

Competitive or allosteric inhibition of the D2 ATPase domain, preventing the mechanical unfolding and translocation of ubiquitinated substrates to the proteasome.