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
  • 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: [email protected].
  • 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: [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. Electronic address: [email protected].
  • 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: [email protected].
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.