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

Zilan Song; Zongjun Xia; Yinchun Ji; Li Xing; Yinglei Gao; Jing Ai; Meiyu Geng; Ao Zhang

doi:10.1016/j.ejmech.2016.04.046

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

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

Authors

Zilan Song¹, Zongjun Xia², Yinchun Ji³, Li Xing¹, Yinglei Gao³, Jing Ai⁴, Meiyu Geng⁵, Ao Zhang⁶

Affiliations

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.

PMID: 27131066
DOI: 10.1016/j.ejmech.2016.04.046

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.

MeSH terms

Administration, Oral
Anaplastic Lymphoma Kinase
Animals
Biological Availability
Carbazoles / administration & dosage
Carbazoles / chemistry*
Carbazoles / pharmacokinetics
Carbazoles / pharmacology*
Cell Line, Tumor
Female
Humans
Mice
Models, Molecular
Protein Conformation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / chemistry
Xenograft Model Antitumor Assays

Substances

Carbazoles
Protein Kinase Inhibitors
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Proto-Oncogene Proteins c-ret
RET protein, human
Receptor Protein-Tyrosine Kinases