VER 155008 is a potent, adenosine-derived inhibitor of the heat shock protein 70 (Hsp70) family, with IC50 values of 0.5μM, 2.6μM, and 2.6μM against Hsp70, heat shock cognate protein 70 (Hsc70), and glucose-regulated protein 78 (Grp78), respectively[1]. VER 155008 exerts its effects by inhibiting Hsp70 ATPase activity, inducing cell cycle arrest, apoptosis, and tumor-specific cell death, and is commonly used in anti-cancer (e.g., prostate and breast cancer) and antiviral research[2,3,4].
In vitro, treatment with VER 155008 (20μM) for 48h in 211H and H28 cells significantly increased the proportion of cells in the G1 phase (from 69.9% to 82.7% in 211H cells; from 77% to 85.2% in H28 cells)[5]. VER 155008 (25μM) treatment in A549 and H1975 cells for 2 days significantly reduced the percentage of 5-bromo-2'-deoxyuridine (BrdU)-positive cells, indicating inhibition of cell proliferation[6].
In vivo, intraperitoneal injection of VER 155008 (40mg/kg; once daily) for two weeks in PC12 tumor-bearing nude mice significantly reduced tumor volume and tumor weight[7]. A single intravenous dose of VER 155008 (25mg/kg) in BALB/c mice resulted in a plasma half-life of 0.6h and a clearance rate of 49mL/min/kg[1].
References:
[1] MASSEY A J, WILLIAMSON D S, BROWNE H, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells[J]. Cancer Chemotherapy and Pharmacology, 2010, 66(3): 535-545.
[2] BUDINA-KOLOMETS A, BALABURSKI G M, BONDAR A, et al. Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition[J]. Cancer Biology & Therapy, 2014, 15(2): 194-199.
[3] WENG J R, HUA C H, CHEN C H, et al. Anti-apoptotic activity of Japanese encephalitis virus NS5 protein in human medulloblastoma cells treated with interferon-β[J]. Journal of Microbiology, Immunology and Infection, 2018, 51(4): 456-464.
[4] YU B, YANG H, ZHANG X, et al. Visualizing and quantifying the effect of the inhibition of HSP70 on breast cancer cells based on laser scanning microscopy[J]. Technology in Cancer Research & Treatment, 2018, 17: 1533033818785274.
[5] SAKAI K, INOUE M, MIKAMI S, et al. Functional inhibition of heat shock protein 70 by VER‐155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism[J]. Thoracic Cancer, 2021, 12(4): 491-503.
[6] WEN W, LIU W, SHAO Y, et al. VER-155008, a small molecule inhibitor of HSP70 with potent anti-cancer activity on lung cancer cell lines[J]. Experimental Biology and Medicine, 2014, 239(5): 638-645.
[7] XU F, LIN D, JIANG W, et al. HSP70 inhibitor VER155008 suppresses pheochromocytoma cell and xenograft growth by inhibition of PI3K/AKT/mTOR and MEK/ERK pathways[J]. International Journal of Clinical and Experimental Pathology, 2019, 12(7): 2585.