2. Academic Validation
  3. Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction

Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction

  • Eur J Med Chem. 2019 Feb 1:163:597-609. doi: 10.1016/j.ejmech.2018.12.018.
Danqi Chen 1,  Yuehong Chen 2,  Fulin Lian 1,  Liu Chen 1,  Yanlian Li 1,  Danyan Cao 1,  Xin Wang 1,  Lin Chen 1,  Jian Li 1,  Tao Meng 1,  Min Huang 3,  Meiyu Geng 2,  Jingkang Shen 1,  Naixia Zhang 4,  Bing Xiong 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: mhuang@simm.ac.cn.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: nxzhang@simm.ac.cn.
  • 5 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: bxiong@simm.ac.cn.
PMID: 30562696 DOI: 10.1016/j.ejmech.2018.12.018
Abstract

Although mutated Ras protein is well recognized as an important drug target, direct targeting Ras has proven to be a daunting task. Recent studies demonstrated that Ras protein needs PDEδ to relocate to plasma membrane to execute its signaling transduction function, which provides a new avenue for modulating the Ras protein. To find small molecules antagonizing the interactions between PDEδ and Ras, here we presented a successful application of fragment-based drug discovery of PDEδ inhibitors. Under the guidance of crystal structures, we are able to quickly optimize the initial fragment into highly potent inhibitors, with more than 2000-fold improvement in binding activity, which further adds to the arsenal towards the inhibition of Ras signaling in Cancer therapy.

Keywords

Fragment-based; Inhibitor; PDEδ-RAS; Protein-protein interaction.

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