title: Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases.
abstract: 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.
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Jiho
authors.initials: J
authors.lastname: Song
authors.affiliation: Life Science Research Institute, Daewoong Pharmaceutical Co., Ltd., Gyeonggi-Do, Republic of Korea.
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Ara
authors.initials: A
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Doran
authors.initials: D
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Hong Khanh
authors.initials: HK
authors.lastname: Nguyen
authors.affiliation: Life Science Research Institute, Daewoong Pharmaceutical Co., Ltd., Gyeonggi-Do, Republic of Korea.
authors.forename: Bong-Yong
authors.initials: BY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000473:pathology; D062105:Molecular Docking Simulation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C516667:pazopanib; C030374:indole; D011494:Protein Kinases; D066246:ErbB Receptors; C030986:pyrimidine