Tanespimycin (17-AAG, KOS953)

Hsp90 derived from tumor cells exhibits a significantly higher binding affinity—approximately 100-fold greater—for Tanespimycin compared to Hsp90 from normal cells. In vitro reconstitution of chaperone complexes with Hsp90 demonstrated an enhanced binding affinity for Tanespimycin, accompanied by an increase in ATPase activity [1]. Tanespimycin induces the degradation of HER2, Akt, and both mutant and wild-type androgen receptor (AR), leading to retinoblastoma-dependent G1 cell cycle arrest in prostate cancer cells [2]. Furthermore, the combination of Tanespimycin and Trastuzumab in ErbB2-overexpressing breast cancer cell lines results in synergistic effects, including enhanced ubiquitination, downregulation of ErbB2 from the cell surface, and subsequent lysosomal degradation [3].

1. Kamal A, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003 Sep 25;425(6956):407-10.
2. Solit DB, et al. 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts.Clin Cancer Res, 2002, 8(5), 986-993.
3. Raja SM, et al. A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells. Cancer Biol Ther. 2008 Oct;7(10):1630-40.