title: Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core.
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.
authors: Department of Pharmacology and Glycobiology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors: Mei
authors: M
authors: Han
authors: Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
authors: Chengyan
authors: C
authors: Wang
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors: Yinchun
authors: Y
authors: Ji
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors: Zilan
authors: Z
authors: Song
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors: Li
authors: L
authors: Xing
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
authors: Yi
authors: Y
authors: Su
authors: Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
authors: Xisheng
authors: X
authors: Wang
authors: 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.
authors: Ao
authors: A
authors: Zhang
authors: 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.
authors: Jing
authors: J
authors: Ai
authors: 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.
authors: Meiyu
authors: M
authors: Geng
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001555:Benzene Derivatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001555:Benzene Derivatives; C072312:ERG protein, human; D047428:Protein Kinase Inhibitors; D000071230:Transcriptional Regulator ERG; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: Antitumor activity; Benzo[b]carbazolone; EML4-ALK kinase; Oxidative metabolism; hERG