The high mortality of colorectal cancer (CRC) is likely caused by early invasion and metastasis. The chemoresistance of tumor cells is the critical reason for treatment failure. The present study aimed to develop targeted solutions to overcome chemotherapy drug resistance in CRC. CCK-8 assay was used to examine SW480 cell viability. SW480 cell apoptosis was examined using flow cytometry. The present study demonstrated that the expression of miR-1271 was significantly decreased in CRC tumors and cell lines compared with control tissues. Furthermore, the expression of microRNA (miR)-1271 was increased and decreased following the transfection of miR-1271 mimics and an inhibitor, respectively. Furthermore, miR-1271 regulated mammalian target of rapamycin (mTOR) expression by directly binding to the mTOR 3'-untranslated region and the relative luciferase activity of mTOR was decreased following miR-1271 overexpression. The results of the present study indicate that miR-1271 may be a potential target for anti-CRC therapy, particularly in the sensitivity of chemotherapeutic drugs. miR-1271 may therefore enhance the sensitivity of CRC cells to chemotherapy drugs and provide a novel approach for the gene therapy of CRC.
V600E is the most common mutation in the B-Raf kinase domain and the B-Raf mutant has been recognized as an attractive target of colorectal cancer. Here, the structural dynamics of V600E-induced conformational conversion in the B-Raf activation loop (A-loop) was characterized in detail using a computational simulation strategy. The simulations revealed that the V600E mutation would induce A-loop flipping from DFG-out to DFG-in, and the approved B-Raf inhibitor vemurafenib exhibits strong selectivity for the mutant over the wild-type kinase. The selectivity is closely associated with the kinase conformation, which can be influenced directly by the V600E mutation. The molecular structure of vemurafenib was applied to a chemical similarity search against a large library of drug/lead-like compounds, from which three hits with high structural similarity were identified, and their inhibitory activities against both the wild-type and mutant kinases were measured by in vitro kinase assay, from which two compounds were determined to possess higher selectivity for the B-Raf mutant than for the wild type (5.2- and 3.1-fold, respectively). They can potently inhibit the kinase mutant with IC = 54 and 76 nM, respectively. Structural analysis suggested that specific noncovalent interactions play a crucial role in the selectivity of B-Raf inhibitors.
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