Valosine-containing protein (VCP)

Valosine-containing protein (VCP), commonly referred to as p97, is a highly conserved member of the AAA+ (ATPases Associated with diverse cellular Activities) family that functions as a molecular segregase [1, 2]. It utilizes the energy from ATP hydrolysis to extract ubiquitinated proteins from macromolecular complexes or membranes, facilitating their degradation by the proteasome or through autophagy [1, 3]. The protein is structured as a hexameric ring with each subunit containing an N-terminal domain and two tandem ATPase domains, D1 and D2; the D2 domain is the primary driver of catalytic activity and the principal target for small-molecule inhibitors [2, 4]. p97 plays a vital role in maintaining cellular proteostasis, particularly through its involvement in endoplasmic reticulum-associated degradation (ERAD) and the DNA damage response [5, 6]. In oncology, p97 is frequently overexpressed to help cancer cells manage high levels of protein synthesis and misfolding stress, making its inhibition a potent strategy to induce apoptosis via the unfolded protein response [2, 8]. Furthermore, mutations in VCP are genetically linked to multisystem proteinopathy, including inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS) [3, 7]. Clinical development is currently focused on second-generation D2-specific inhibitors like CB-5339, which aim to provide therapeutic efficacy in hematological and solid tumors while avoiding the off-target ocular toxicities associated with earlier compounds [4, 8]. Sources: [1] UniProt Consortium, P55072 (VCP_HUMAN). [2] Anderson, D. J., et al. (2015). Cancer Cell, 28(5), 653-665. [3] Tang, W. K., & Xia, D. (2016). IUBMB Life, 68(9), 736-748. [4] Cleary, J. M., et al. (2020). Journal of Clinical Oncology, 38(15_suppl), 3543. [5] Meyer, H., et al. (2012). Journal of Cell Science, 125(10), 2311-2320. [6] Deshaies, R. J. (2014). BMC Biology, 12, 94. [7] Watts, G. D., et al. (2004). Nature Genetics, 36(4), 377-381. [8] Huryn, D. M., et al. (2020). Chemical Reviews, 120(10), 4497-4551.

Other names

p97Transitional endoplasmic reticulum ATPaseTER ATPaseCDC48D15KLS1

Selective competitive or allosteric inhibition of the D2 ATPase domain to prevent the mechanical unfolding and translocation of ubiquitinated substrates, thereby inducing lethal proteotoxic stress and the unfolded protein response.