2. Academic Validation
  3. Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity

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.
Mingze Qin 1,  Ye Tian 2,  Xiao Han 3,  Qi Cao 2,  Shuaishuai Zheng 2,  Chunyang Liu 2,  Xia Wu 2,  Lei Liu 2,  Yangyang Meng 2,  Xiaobo Wang 4,  Haotian Zhang 5,  Yunlei Hou 6
Affiliations

Affiliations

  • 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: wxbbenson0653@sina.com.
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhanghaotian2087@163.com.
  • 6 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: houyunlei901202@163.com.
PMID: 32305182 DOI: 10.1016/j.bmc.2020.115486
Abstract

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.

Keywords

Antitumor activity; Multi-kinase inhibitor; Structural modification.

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