NT157(http://www.sun-shinechem.com/Details/NT-157/974/1384426-12-3.html) is a small-molecule tyrphostin targeting human IRSes (Reuveni et al.,2013), using androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. The effect of NT157 on cell growth and apoptosis in vitro was examined by crystal violet assay, flow cytometry, and expression and activation state of downstream signaling targets was examined by immunoblotting. In vivo growth of subcutaneous xenografts was performed in nude mice treated with intraperitoneally administered NT157 or DMSO by measuring tumor volume of PC3 xenografts in intact mice, and tumor volume and serum prostate-specific antigen levels in castrated mice harboring LNCaP xenografts. We observed dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF-1-induced AKT activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing apoptosis of LNCaP cells and increasing G2M arrest in PC3 cells. NT157 suppressed androgen-responsive growth, delayed CRPC progression of LNCaP xenografts and suppressed PC3 tumor growth alone and in combination with docetaxel. Conclusion: This study reports the first preclinical proof-of-principle data that this novel small-molecule tyrosine kinase inhibitor targeting human IRS suppresses IRS1/2 expression, delays CRPC progression, and suppresses growth of CRPC tumors in vitro and in vivo.
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