CB-5083 is a highly selective and orally bioavailable AAA-ATPase p97 inhibitor with an IC50 value of 11nM[1]. P97 is an enzyme involved in clearing misfolded proteins. CB-5083 binds to and inhibits p97 activity, leading to accumulation of ubiquitinated proteins, inducing prototoxic stress and activating apoptosis to exert anti-tumor activity (Fig 1)[2]. CB-5083 is commonly used as an anti-cancer agent in research on multiple myeloma and solid tumor models[3,4].
Fig 1. Mechanism of action of CB-5083[5,6]. CB-5083 specifically targets the Valosin-Containing Protein (VCP) p97. By inhibiting the ATPase activity of p97, CB-5083 blocks the ubiquitin-proteasome system and endoplasmic reticulum-associated protein degradation (ERAD), leading to the accumulation of misfolded and damaged proteins. This subsequently triggers the unfolded protein response and prototoxic stress, ultimately resulting in cancer cell death.
In vitro, treatment of myeloma RPMI8226 cells with CB-5083 (0.3125-20μM) for 8h induced expression of unfolded protein response (UPR) markers sXBP1 and BiP, and accumulation of K48 polyubiquitinated proteins[5]. Treatment of human osteosarcoma SJSA-1 and U2OS cells with CB-5083 (0.5, 1 μM) for 48h induced G1 phase cell cycle arrest and promoted apoptosis[7]. Treatment of THP-1 and MV4-11 cells with CB-5083 (200nM) for 6h altered the ubiquitin-modified proteome, including ubiquitination levels of Valosin-containing protein (VCP) itself, proteasome components, autophagy-related proteins, and DNA damage response factors[8].
In vivo, oral administration of CB-5083 (60mg/kg) to severe combined immunodeficiency disease (SCID) beige mice bearing RPMI8226 xenografts resulted in plasma levels of CB-5083 within 2-20μM over 24h, sustained significant K48 polyubiquitinated protein accumulation, activated UPR, and increased CHOP protein expression by 2.7-fold compared to baseline[5]. Oral gavage of CB-5083 (15mg/kg) to 2-month-old VCPR155H/R155H homozygous mice for 5 months was well tolerated, with steady body weight gain and normal organ weights, did not increase liver enzymes (such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), and significantly reduced AST levels[9].
References:
[1] ZHOU H J, WANG J, YAO B, et al. Discovery of a first-in-class, potent, selective, and orally bioavailable inhibitor of the p97 AAA ATPase (CB-5083)[J]. 2015.
[2] ANDERSON D J, LE MOIGNE R, DJAKOVIC S, et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis[J]. Cancer Cell, 2015, 28(5): 653-665.
[3] LEBLANC A K, MAZCKO C N, FAN T M, et al. Comparative oncology assessment of a novel inhibitor of valosin-containing protein in tumor-bearing dogs[J]. Molecular Cancer Therapeutics, 2022, 21(10): 1510-1523.
[4] WANG F, LI S, HOUERBI N, et al. Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition[J]. Cell Chemical Biology, 2022, 29(3): 517-529.
[5] LE MOIGNE R, AFTAB B T, DJAKOVIC S, et al. The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma[J]. Molecular Cancer Therapeutics, 2017, 16(11): 2375-2386.
[6] CB-5083 is a selective and orally bioavailable p97 inhibitor[EB/OL]. (2020-12-17) [2025-10-02]. https://www.immune-system-research.com/2020/12/17/cb-5083-is-a-selective-and-orally-bioavailable-p97-inhibitor/.
[7] ZHAO Z, WU M, ZHANG X, et al. CB-5083, an inhibitor of P97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis[J]. American Journal of Translational Research, 2020, 12(6): 2956.
[8] SZCZĘŚNIAK P P, HEIDELBERGER J B, SERVE H, et al. VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells[J]. PLoS One, 2022, 17(4): e0266478.
[9] CHENG C, WEISS L, LEINONEN H, et al. VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy[J]. Journal of Translational Medicine, 2022, 20(1): 21.