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

Mei Han; Chengyan Wang; Yinchun Ji; Zilan Song; Li Xing; Yi Su; Xisheng Wang; Ao Zhang; Jing Ai; Meiyu Geng

doi:10.1016/j.bmcl.2016.10.039

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. Epub 2016 Oct 14.

Authors

Mei Han¹, Chengyan Wang², Yinchun Ji³, Zilan Song⁴, Li Xing⁴, Yi Su³, Xisheng Wang², Ao Zhang⁵, Jing Ai⁶, Meiyu Geng⁷

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.

MeSH terms

Administration, Oral
Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Benzene Derivatives / chemistry*
Benzene Derivatives / pharmacokinetics
Benzene Derivatives / pharmacology*
Benzene Derivatives / therapeutic use
Cell Line, Tumor
Drug Discovery
Humans
Mice
NIH 3T3 Cells
Neoplasms / drug therapy
Neoplasms / enzymology
Neoplasms / metabolism
Oxidation-Reduction
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Transcriptional Regulator ERG / metabolism

Substances

Antineoplastic Agents
Benzene Derivatives
ERG protein, human
Protein Kinase Inhibitors
Transcriptional Regulator ERG
ALK protein, human
Alk protein, mouse
Alk protein, rat
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases