Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases

• Published in: PloS one 2015-09, Vol.10 (9), p.e0138823
• Main Authors: Song, Jiho, Yoo, Jakyung, Kwon, Ara, Kim, Doran, Nguyen, Hong Khanh, Lee, Bong-Yong, Suh, Wonhee, Min, Kyung Hoon
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Antiangiogenic agents; Antiangiogenics; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - pathology; Cell migration; Cell proliferation; Cell Proliferation - drug effects; Chemical compounds; Chemotherapy; Derivatives; Development and progression; Docking; Drug dosages; Drug therapy; Endothelial cells; Epidermal growth factor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Indazoles; Indoles; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Inhibitory Concentration 50; Kinases; Life assessment; Life sciences; Lung cancer; Lung Neoplasms - pathology; Metastasis; Molecular Docking Simulation; Neovascularization, Pathologic - drug therapy; Non-small cell lung cancer; Pazopanib; Penicillin; Pharmacology; Pharmacy; Physiological aspects; Properties; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - metabolism; Proteins; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Structure-Activity Relationship; Structure-activity relationships; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tumors; Umbilical vein; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - pharmacology; Vascular endothelial growth factor receptor 2
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0138823

Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.