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

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.
Xiaolong Jiang 1,  Ji Zhou 2,  Jing Ai 3,  Zilan Song 4,  Xia Peng 2,  Li Xing 4,  Yong Xi 2,  Junfeng Guo 4,  Qizheng Yao 5,  Jian Ding 2,  Meiyu Geng 6,  Ao Zhang 7
Affiliations

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.

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