Identification of Novel Anaplastic Lymphoma Kinase (ALK) Inhibitors Using a Common Feature Pharmacophore Model Derived from Known Ligands Crystallized with ALK

Authors

  • Huan-Zhang Xie,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
    2. West China School of Pharmacy, Sichuan University, Sichuan 610041, China
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    • These authors contributed equally to this work.

  • Hai Lan,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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    • These authors contributed equally to this work.

  • You-Li Pan,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Jun Zou,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Ze-Rong Wang,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
    2. West China School of Pharmacy, Sichuan University, Sichuan 610041, China
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  • Lin-Li Li,

    Corresponding author
    1. West China School of Pharmacy, Sichuan University, Sichuan 610041, China
      Corresponding authors: Lin-Li Li and Sheng-Yong Yang, ysylilinli@sina.com ; yangsy@scu.edu.cn
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  • Qi Huang,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Hui Zhang,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Sheng-Yong Yang

    Corresponding author
    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
      Corresponding authors: Lin-Li Li and Sheng-Yong Yang, ysylilinli@sina.com ; yangsy@scu.edu.cn
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Corresponding authors: Lin-Li Li and Sheng-Yong Yang, ysylilinli@sina.com ; yangsy@scu.edu.cn

Abstract

In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co-crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping-check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant-driven cancer cell line, Karpas299. And six of them showed a good anti-viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508-5181 (from Specs), which gave a half maximal inhibitory concentration (IC50) of 5.3 μm.

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