SHP-1 was selleck products first identified in hematopoietic cells and is an important regulator of various biological processes in lymphocytes.[15] However, the underlying molecular mechanism by

which SHP-1 affects carcinogenesis is still poorly understood. In leukemia and lymphoma cell lines, SHP-1 is believed to function as a tumor suppressor, as evidenced by decreased levels of protein and messenger RNA.[13, 16] SHP-1 is also believed to play a suppressive role in other tumors, such as in estrogen-receptor-negative breast cell lines.[16] However, in some solid tumors, such as prostate cancer,[17, 18] ovarian cancer,[19] and breast cell lines,[20, 21] overexpression of SHP-1 accompanied aggressive tumor progression. Interestingly, SHP-2, which shares almost 70% sequence similarity with SHP-1, was recently reported to have a novel tumor-suppressor function in HCC.[22] Notably, we did not find that sorafenib or SC compounds significantly induced the induction of SHP-2 activity in HCC cells and in purified SHP-2 proteins. In addition to D61, several critical sites of inhibitory N-SH2 domain, which are also involved in blocking the WPD loop to form autoinhibited structure, are different between SHP-1 and SHP-2, such as S59 and F62 in SHP-1 and T59 and Y62 in SHP-2. The further investigation of molecular discrimination between SHP-1 and SHP-2 will be helpful

to improve sorafenib-related clinical studies. The crystal structure of the ligand-free SHP-1 protein has an autoinhibition formation dependent on the inhibitory

learn more effect of the N-SH2 domain on the catalytic PTP domain.[10-12] Of note, the specific residue, D61, forms a critical salt bridge resulting in a “closed” catalytic PTP domain. Having clarified the molecular mechanism by which sorafenib affects SHP-1 in HCC, we then attempted to engineer novel sorafenib derivatives with elevated SHP-1 activity to analyze their anti-HCC effect. After screening, SC-43 and SC-40 were characterized to have better biological effects than sorafenib in HCC with more potent SHP-1 activity. We found significant induction of SHP-1 activity in purified nearly SHP-1 protein after treatment with SC-43 or SC-40, compared to sorafenib. The molecular docking between SC derivatives and SHP-1 crystal structure proposed a binding to the N-SH2 domain and further releasing of the PTP domain in SHP-1, which provided a molecular foundation for the present structure-based optimization. SC-43 and SC-40 exerted better biological effects on HCC cells and were effective in HCC cells that were resistant to sorafenib. In conclusion, in this study, we demonstrated that sorafenib affects SHP-1 activity by impairing the inhibitory N-SH2 domain to release SHP-1. New sorafenib derivatives have been developed as better anti-HCC agents by targeting SHP-1.