2. Academic Validation
  3. Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core

Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core

  • Bioorg Med Chem Lett. 2016 Nov 15;26(22):5399-5402. doi: 10.1016/j.bmcl.2016.10.039.
Mei Han 1,  Chengyan Wang 2,  Yinchun Ji 3,  Zilan Song 4,  Li Xing 4,  Yi Su 3,  Xisheng Wang 2,  Ao Zhang 5,  Jing Ai 6,  Meiyu Geng 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Glycobiology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2 Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, 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 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 CAS Key Laboratory of Receptor 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: aozhang@simm.ac.cn.
  • 6 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: jai@simm.ac.cn.
  • 7 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: mygeng@simm.ac.cn.
PMID: 27769623 DOI: 10.1016/j.bmcl.2016.10.039
Abstract

A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor.

Keywords

Antitumor activity; Benzo[b]carbazolone; EML4-ALK kinase; Oxidative metabolism; hERG.

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