Discovery of a potent tyrosine kinase AXL inhibitor bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core

Yueliang Wang; Li Xing; Yinchun Ji; Jiqing Ye; Yang Dai; Wangting Gu; Jing Ai; Zilan Song

doi:10.1016/j.bmcl.2019.01.018

Discovery of a potent tyrosine kinase AXL inhibitor bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core

Bioorg Med Chem Lett. 2019 Mar 15;29(6):836-838. doi: 10.1016/j.bmcl.2019.01.018. Epub 2019 Jan 21.

Authors

Yueliang Wang¹, Li Xing², Yinchun Ji³, Jiqing Ye², Yang Dai³, Wangting Gu², Jing Ai⁴, Zilan Song⁵

Affiliations

¹ Shanghai Key Laboratory of Bio-Energy Crops, School of Life Sciences, Shanghai University, Shanghai 200444, China; Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
² CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
³ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
⁵ CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].

PMID: 30685094
DOI: 10.1016/j.bmcl.2019.01.018

Abstract

Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC₅₀ values of 1.2 and 0.3 nM, respectively. Compared with the reference compound 5, our new discovered AXL inhibitor 15c is more potent in both assays.

Keywords: AXL Kinase; Cancer; Pyrazine.

Publication types

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

MeSH terms

Aniline Compounds / chemistry
Aniline Compounds / pharmacology
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Benzazepines / chemical synthesis
Benzazepines / pharmacokinetics
Benzazepines / pharmacology*
Cell Line, Tumor
Drug Discovery
Mice
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacokinetics
Pyrazines / pharmacology*
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

Aniline Compounds
Antineoplastic Agents
Benzazepines
Protein Kinase Inhibitors
Pyrazines
gilteritinib
Axl protein, rat
Receptor Protein-Tyrosine Kinases