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Eur J Med Chem. 2016 Aug 8;118:244-9. doi: 10.1016/j.ejmech.2016.04.046. Epub 2016 Apr 19.

An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core.

Author information

1
CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
2
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, 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. Electronic address: jai@simm.ac.cn.
5
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China. Electronic address: mygeng@simm.ac.cn.
6
CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: aozhang@simm.ac.cn.

Abstract

Our early structure-activity relationship study has identified benzo[b]carbazolone 6 as a high potency orally bioavailable ALK inhibitor. Further lead profiling disclosed that 6 is active against both ALK resistant and hot spot-activating mutants, and is also highly potent against RET kinase. Tumor stasis and partial tumor regression were achieved with 6 in both NIH/3T3-EML4-ALK and NIH/3T3-EML4-ALK L1196M xenograft models. Based on the optimal in vitro and in vivo antitumor efficacy, compound 6 is now being profiled further in our preclinical settings as a new orally available ALK/RET dual inhibitor.

KEYWORDS:

ALK inhibitors; Antiresistance; Benzo[b]carbazolones; Non-small-cell lung cancer; Preclinical study; RET kinase

PMID:
27131066
DOI:
10.1016/j.ejmech.2016.04.046
[Indexed for MEDLINE]

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