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

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.
Zilan Song 1,  Zongjun Xia 2,  Yinchun Ji 3,  Li Xing 1,  Yinglei Gao 3,  Jing Ai 4,  Meiyu Geng 5,  Ao Zhang 6
Affiliations

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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z