Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity
- Bioorg Med Chem. 2020 Jun 1;28(11):115486. doi: 10.1016/j.bmc.2020.115486.
- 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Chinese People's Liberation Army Logistics Support Force No. 967 Hospital, Dalian 116021, PR China.
- 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
- 3. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
- 4. Chinese People's Liberation Army Logistics Support Force No. 967 Hospital, Dalian 116021, PR China. Electronic address: [email protected].
- 5. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
- 6. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
Structural modifications of compound 2, an angiokinase inhibitor reported by our group were performed, which led to the discovery of methyl (Z)-3-(((4-(2-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrrol-1-yl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (7h). Compound 7h exhibited excellent inhibitory activity against angiokinases including VEGFR-1/2/3, PDGFRα/β, and FGFR-1, as well as Lyn and c-Kit kinases. At the cellular level, compound 7h significantly attenuated phosphorylation of Akt and ERK proteins, potently inhibited colony formation of HT-29, MKN74, and HepG2 Cancer cells, and induced cell Apoptosis. Upon incubation with human liver microsome, 7h exhibited comparable metabolic stability to nintedanib. Compound 7h has emerged as a promising lead compound for future drug design.