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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.