Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity

Mingze Qin; Ye Tian; Xiao Han; Qi Cao; Shuaishuai Zheng; Chunyang Liu; Xia Wu; Lei Liu; Yangyang Meng; Xiaobo Wang; Haotian Zhang; Yunlei Hou

doi:10.1016/j.bmc.2020.115486

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. Epub 2020 Apr 3.

Authors

Mingze Qin¹, Ye Tian², Xiao Han³, Qi Cao², Shuaishuai Zheng², Chunyang Liu², Xia Wu², Lei Liu², Yangyang Meng², Xiaobo Wang⁴, Haotian Zhang⁵, Yunlei Hou⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, Nude
Molecular Docking Simulation
Molecular Structure
Oxindoles / chemical synthesis
Oxindoles / chemistry
Oxindoles / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / metabolism*
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Oxindoles
Protein Kinase Inhibitors
Pyrroles
Protein Kinases