ponatinib and nintedanib

Pursuing on our efforts regarding development of novel multikinase inhibitors, herein we report the design and synthesis of novel 2-indolinone-based ureides 6a-u and amides 10a-j. In this work we adopt a hybridization strategy between type IIA PTK inhibitor (sorafenib) and type IIB PTK inhibitors (sunitinib and nintedanib). This was implemented via linking the indolinone core, in both sunitinib and nintedanib, which is well-fitted in the hinge region in the kinase domain front cleft and the biaryl urea extension, in sorafenib, which is accommodated in the gate area and the hydrophobic back pocket. Molecular docking of the designed hybrid compounds in VEGFR-2 and FGFR-1 active sites revealed, as planned, their ability to establish the binding interactions achieved by both original type IIA and type IIB inhibitors. The designed compounds were evaluated for their multikinase inhibitory activity towards VEGFR-2, PDGFR-b and FGFR-1 and anti-proliferative activity towards HepG2, MCF-7, A549 and A498 cancer cell lines. The ureido analogue 6u emerged as the most potent multikinase inhibitor in the ureido series with VEGFR-2, FGFR-1 and PDGFR-b IC

Topics: Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Indoles; Models, Molecular; Oxindoles; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor beta; Sorafenib; Structure-Activity Relationship; Sunitinib; TYK2 Kinase; Vascular Endothelial Growth Factor Receptor-2