17-DMAG (Alvespimycin) HCl is an effective inhibitor of Hsp90, with an IC50 value of 62nM [1]. 17-DMAG (Alvespimycin) HCl binds to the ATP binding motif of Hsp90 and inhibits its protein folding protection activity, resulting in the misfolding and degradation of the target proteins of Hsp90 (such as EGFR, AKT, mutant p53 and IKK) [2]. 17-DMAG (Alvespimycin) HCl has anti-tumor effects and can be used in cancer research such as lung cancer, liver cancer, and colon cancer [3-4].
In vitro, 17-DMAG (Alvespimycin) HCl (50-500nM; 24 or 48h) treatment significantly and dose- and time-dependently led to depletion of the target protein IKK in chronic lymphocytic leukemia (CLL) cells and cysteine aspartate-dependent apoptosis, reducing the binding of NF-κB p50/p65 DNA and the transcription of NF-κB target genes [5]. 17-DMAG (Alvespimycin) HCl (0-1000nM; 24h) treatment inhibits the proliferation of osteosarcoma cells in a dose-dependent manner and inhibits the activation of MET protein and the cell cycle progression [6].
In vivo, 17-DMAG (Alvespimycin) HCl (10mg/kg/day; 5 times per week for 16 days; i.p.) treatment significantly reduces the number of white blood cells in the blood of TCL1-SCID transgenic mouse models and prolongs survival [5]. The treatment with 17-DMAG (Alvespimycin) HCl (5mg/kg/day; 3 times per week; i.p.) reduced the incidence and severity of abdominal aortic aneurysms induced by ANG II in mice, weakened the remodeling of the aortic wall, the inflammatory response and the formation of new blood vessels, and decreased the expression of MMP-2 and MMP-9, the level of MDA and the secretion of MCP-1 [7].
References:
[1] Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem. 2006;49(15):4606-4615.
[2] Sun X, Bristol JA, Iwahori S, Hagemeier SR, Meng Q, Barlow EA, Fingeroth JD, Tarakanova VL, Kalejta RF, Kenney SC. Hsp90 inhibitor 17-DMAG decreases expression of conserved herpesvirus protein kinases and reduces virus production in Epstein-Barr virus-infected cells. J Virol. 2013 Sep;87(18):10126-38.
[3] Chang Y J, Huang C Y, Hung C S, et al. Glucose-regulated protein 78 mediates the therapeutic efficacy of 17-DMAG in colon cancer cells[J]. Tumor Biology, 2015, 36(6): 4367-4376.
[4] Mellatyar H, Talaei S, Pilehvar-Soltanahmadi Y, et al. Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art[J]. Biomedicine & Pharmacotherapy, 2018, 102: 608-617.
[5] Hertlein E, Wagner AJ, Jones J, et al. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood. 2010;116(1):45-53.
[6] Kawano M, Tanaka K, Itonaga I, Iwasaki T, Kubota Y, Tsumura H. The anti-oncogenic effect of 17-DMAG via the inactivation of HSP90 and MET pathway in osteosarcoma cells. Oncol Res. 2023 Jul 21;31(5):631-643.
[7] Qi J, Yang P, Yi B, et al. Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2015, 308(8): H841-H852.