SC-60, a dimer-based sorafenib derivative, shows a better anti-HCC effect than sorafenib in a preclinical HCC model
Menée in vitro et in vivo, cette étude montre qu'un composé appelé SC-60, dérivé du sorafenib, permet de surmonter une résistance au sorafenib dans le traitement d'un carcinome hépatocellulaire
Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that SC-60, a dimer-based sorafenib derivative, overcomes the resistance of sorafenib and shows a better anti-HCC effect in vitro and in vivo. SC-60 substantially increased SHP-1 phosphatase activity in HCC cells and purified SHP-1 proteins, suggesting that SC-60 affects SHP-1 directly. Molecular docking and truncated mutants of SHP-1 further confirmed that SC-60 interferes with the inhibitory N-SH2 domain to relieve the closed catalytic PTP domain of SHP-1. Deletion of N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of SC-60 on SHP-1, p-STAT3 and apoptosis. Importantly, SC-60 exhibited significant survival benefits compared to sorafenib in an HCC orthotopic model via targeting the SHP-1/STAT3-related signaling pathway. In summary, dimer derivative of sorafenib, SC-60, is a SHP-1 agonist and may be a potent reagent for HCC targeted therapy.
http://mct.aacrjournals.org/content/early/2013/11/23/1535-7163.MCT-13-0595.abstract