2. Academic Validation
  3. Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

  • Eur J Med Chem. 2018 Jan 20:144:386-397. doi: 10.1016/j.ejmech.2017.12.060.
Kaijun Geng 1,  Zongjun Xia 2,  Yinchun Ji 3,  Ruisi Ruthy Zhang 4,  Deqiao Sun 2,  Jing Ai 5,  Zilan Song 6,  Meiyu Geng 2,  Ao Zhang 7
Affiliations

Affiliations

  • 1 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, NO.19A Yuquan Road, Beijing 100049, 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, NO.19A Yuquan Road, 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 Shanghai International Studies University Bilingual School, Grade 12, Class I, Shanghai 200083, China.
  • 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; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
  • 6 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. Electronic address: songalan@simm.ac.cn.
  • 7 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; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
PMID: 29288940 DOI: 10.1016/j.ejmech.2017.12.060
Abstract

To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diarylaminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors.

Keywords

2,4-Diarylaminopyrimidine; ALK; Drug resistance; G1202R mutant; Resorcinol.

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