Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: design, synthesis, and structure-activity relationship study

Xiaolong Jiang; Ji Zhou; Jing Ai; Zilan Song; Xia Peng; Li Xing; Yong Xi; Junfeng Guo; Qizheng Yao; Jian Ding; Meiyu Geng; Ao Zhang

doi:10.1016/j.ejmech.2015.10.005

Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: design, synthesis, and structure-activity relationship study

Eur J Med Chem. 2015 Nov 13:105:39-56. doi: 10.1016/j.ejmech.2015.10.005. Epub 2015 Oct 9.

Authors

Xiaolong Jiang¹, Ji Zhou², Jing Ai³, Zilan Song⁴, Xia Peng², Li Xing⁴, Yong Xi², Junfeng Guo⁴, Qizheng Yao⁵, Jian Ding², Meiyu Geng⁶, Ao Zhang⁷

Affiliations

¹ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, 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.
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. Electronic address: jai@simm.ac.cn.
⁴ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: qz_yao@163.com.
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. Electronic address: mygeng@simm.ac.cn.
⁷ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: aozhang@simm.ac.cn.

PMID: 26476749
DOI: 10.1016/j.ejmech.2015.10.005

Abstract

Four series of tetracyclic benzo[b]carbazolone compounds possessing more rotatable bonds and higher molecular flexibility were designed by either inserting a linker within the C8-side chain or by opening the middle ketone ring on the basis of compound 5 (Alectinib, CH5424802). Compound 15b was identified showing nearly identical high potency against both wild-type and the gatekeeper mutant ALK kinase (3.4 vs 3.9 nM). This compound has favorable PK profile with an oral bioavailability of 67.1% in rats. Moreover, compound 15b showed significant growth inhibition against ALK driven cancer cells and KARPAS-299 xenograft model.

Keywords: ALK inhibitors; Anti-cancer; Anti-resistance; Benzo[b]carbazolones; Non-small-cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Biological Availability
Carbazoles / administration & dosage
Carbazoles / chemistry
Carbazoles / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, SCID
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbazoles
Protein Kinase Inhibitors
ALK protein, human
Alk protein, mouse
Alk protein, rat
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases