title: Synthesis and in vivo SAR study of indolin-2-one-based multi-targeted inhibitors as potential anticancer agents.
abstract: A series of indolin-2-one analogues were designed and synthesized, and all of them exhibited excellent in vitro potency. The structure and in vivo activity or toxicity relationship (in-vivo SAR) investigation of indolin-2-one structural analogues was carried out. In vivo efficacy studies indicated that 3b significantly suppressed tumor growth in HT-29 and NCI-H460 xenografts without causing significant loss of body weight. Kinase assay showed that compound 3b effectively inhibited the VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-β kinases, but had little effect on the VEGFR-1 kinase. Besides, 3b showed higher selectivity for VEGFR-2 compared with PDGFR-β. On the basis of its selectivity and safety properties, 3b was identified as a drug candidate for the treatment of cancer.
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Haojie
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Xingjiang
authors.initials: X
authors.lastname: Gong
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Shuyong
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China. Electronic address: chuanwen.fan@qilu-pharma.com.
authors.forename: Chuanwen
authors.initials: C
authors.lastname: Fan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C456900:indolin-2-one; D011494:Protein Kinases; D000077210:Sunitinib
keywords: In-vivo SAR; Indolin-2-one analogues; Multi-targeted inhibitors; PDGFR-β; VEGFR-2