CB-5339 is a potent and selective, orally bioavailable small molecule inhibitor of valosin containing protein (VCP)/p97, with an IC50 value of 9nM[1]. CB-5339 targets the D2 ATPase domain of p97, effectively inhibiting p97 function, triggering the accumulation of ubiquitinated proteins, and inducing proteotoxic stress[2]. CB-5339 has been widely used as an anti-cancer agent to inhibit the proliferation of solid tumors and hematological tumors[3].
In vitro, CB-5339 treatment for 72 hours significantly inhibited the proliferation of HCT-116 cells, with an IC50 value of 0.7±0.07μM[4]. After 48 hours of treatment with CB-5339, the viability of 17-71 cells and DH82 cells was significantly inhibited, with IC50 values of 188nM and 486nM, respectively[5]. Treatment with 2μM CB-5339 for 7 days significantly induced senescence in RBE cells[6].
In vivo, CB-5339 treatment (90mg/kg; p.o.) for 4 days reduced the number of circulating leukemia cells in the MLL-AF9 syngeneic mouse model and prolonged the survival time of the mice[7]. CB-5339 (50mg/kg/day; p.o.) combined with venetoclax (30mg/kg/day; p.o.) for 3 weeks significantly reduced the acute myelocytic leukemia (AML) burden in NSG mice, and increased the median survival time and overall survival time, without causing obvious toxicity[8].
References:
[1] Kilgas S, Ramadan K. Inhibitors of the ATPase p97/VCP: From basic research to clinical applications[J]. Cell Chemical Biology, 2023, 30(1): 3-21.
[2] Carrera Espinoza M J, Tucker S K, Sureshkumar S, et al. Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics[J]. Cancers, 2025, 17(18): 2945.
[3] Benajiba L, Carraway H E, Hamad N, et al. Trials in progress: a phase I study to evaluate the safety and pharmacokinetic profiles of CB-5339 in participants with relapsed/refractory acute myeloid leukemia or relapsed/refractory intermediate or high-risk myelodysplastic syndrome[J]. Blood, 2020, 136: 21.
[4] Wang X, Wen T, Miao H, et al. Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer[J]. Bioorganic & Medicinal Chemistry, 2022, 74: 117050.
[5] 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.
[6] Yang W, Wang S, Ji S, et al. CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma[J]. Proceedings of the National Academy of Sciences, 2025, 122(39): e2519568122.
[7] Roux B, Vaganay C, Vargas J D, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor[J]. Science translational medicine, 2021, 13(587): eabg1168.
[8] Fiskus W C, Das K, Mill C P, et al. Efficacy of Vcp/p97 inhibitor, CB-5339, alone and in combinations against high-risk AML, including those with genetic lesion in TP53[J]. 2022.