Synthesis and in vivo SAR study of indolin-2-one-based multi-targeted inhibitors as potential anticancer agents

• Series of indolin-2-one analogues with potent anti-angiogenesis were synthesized.
• The in-vivo SAR of these indolin-2-one analogues was described.
• Compared with sunitinib, a safer multi-targeted inhibitor 3b had been discovered.
• 3b was an effective inhibitor of VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-β.
• 3b exhibited higher selectivity for the VEGFR-2 compared with PDGFR-β or VEGFR-1.

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.

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