2. Academic Validation
  3. Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities

Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities

  • J Med Chem. 2023 Oct 20. doi: 10.1021/acs.jmedchem.3c01090.
Lili Feng 1,  Xiang Chen 1,  Gang Sheng 1,  Yingchun Li 1,  Yingying Li 1,  Yixuan Zhang 2,  Kun Yao 3,  Zhouyue Wu 1,  Rong Zhang 1,  Takayuki Kiboku 4,  Atsushi Kawasaki 4,  Katsuhisa Horimoto 4 5,  Yamin Tang 1,  Meiling Sun 6,  Feng Han 1 2 7,  Dongyin Chen 1
Affiliations

Affiliations

  • 1 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 2 Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China.
  • 3 Laboratory of Medicinal Chemical Biology, Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, China.
  • 4 Socium Inc., Tokyo 1350064, Japan.
  • 5 Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 1350064, Japan.
  • 6 Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 7 Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China.
PMID: 37861443 DOI: 10.1021/acs.jmedchem.3c01090
Abstract

Glioblastoma is the most common brain tumor, with high recurrence and low survival rates. An integrative bioinformatics analysis demonstrated that anaplastic lymphoma kinase (ALK) is a promising therapeutic target for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole derivatives, which were further evaluated for antiproliferative activity using glioma cell lines. Among them, compound 4a significantly inhibited the viability of glioblastoma cells. With favorable pharmacokinetic characteristics and blood-brain barrier permeability, 4a improved the survival rate and inhibited the growth of orthotopic glioblastoma. The Phospho-Totum system revealed that ALK was a potential target for the antiglioblastoma activity of 4a. Further experiments indicated that 4a might be a novel ALK modulator, which interacted with the extracellular ligand-binding domain of ALK, thus selectively induced ERK-mediated Autophagy and Apoptosis. Our findings provide an alternative ALK-based targeting strategy and a new drug candidate for glioblastoma therapy.

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