Conteltinib

Focal adhesion kinase (FAK), a multi-functional cytoplasmic tyrosine kinase, plays a critical role in cancer migration, proliferation and metastasis via regulating multiple signaling pathways. SY-707 is an anaplastic lymphoma kinase (ALK)/FAK/type 1 insulin-like growth factor receptor (IGF1R) multi-kinase inhibitor which is now being evaluated in phase II clinical trials for ALK positive non-small cell lung cancer (NSCLC). However, the effect of SY-707 on breast cancer is unknown. In this study, we assessed preclinical the anti-growth and anti-metastasis potency of SY-707 in breast cancer cells. ATP content, PE-Annexin V, and would healing assays were used to examine cell proliferation, cell cycle and migration. Then, SD rat and beagle dog models were used to evaluate the pharmacokinetics profile of SY-707, and mouse xenograft model was used to evaluate the anti-cancer activities of SY-707 . We found that breast cancer cells apoptosis were induced by SY-707. Moreover, SY-707 exerted inhibition on cell migration and adhesion in a dose-dependent manner. In T47D xenograft mice, SY-707 had significant anti-tumor activities alone or synergistically with Paclitaxel. Meanwhile, SY-707 also displayed significant suppression on spontaneous metastasis of tumor to the lung in 4T1 murine breast cancer xenograft model. In conclusion, SY-707 has potent anti-proliferation and anti-migration potential in breast cancer and , implying its therapeutic application for the treatment of breast cancer in future clinical trials.

Focal adhesion kinase (FAK) is a promising target for developing more effective anticancer drugs.To better understand the structure-activity relationships and mechanism of actions of FAK inhibitors, a mol. modeling study using 3D-QSAR, mol. docking, mol. dynamics simulations, and binding free energy anal. were conducted.Two types of satisfactory 3D-QSAR models were generated, comprising the CoMFA model (R2cv = 0.528, R2pred = 0.7557) and CoMSIA model (R2cv = 0.757, R2pred = 0.8362), for predicting the inhibitory activities of novel inhibitors.The derived contour maps indicate structural characteristics for substituents on the template.Mol. docking, mol. dynamic simulations and binding free energy calculations further reveal that the binding of inhibitors to FAK is mainly contributed from hydrophobic, electrostatic and hydrogen bonding interactions.In addition, some key residues (Arg14, Glu88, Cys90, Arg138, Asn139, Leu141, and Leu155) responsible for ligand-receptor binding are highlighted.All structural information obtained from 3D-QSAR models and mol. dynamics is consist with the available exptl. activities.All the results will facilitate the optimization of this series of FAK inhibitors with higher inhibitory activities.