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

Danqi Chen; Yuehong Chen; Fulin Lian; Liu Chen; Yanlian Li; Danyan Cao; Xin Wang; Lin Chen; Jian Li; Tao Meng; Min Huang; Meiyu Geng; Jingkang Shen; Naixia Zhang; Bing Xiong

doi:10.1016/j.ejmech.2018.12.018

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. Epub 2018 Dec 11.

Authors

Danqi Chen¹, Yuehong Chen², Fulin Lian¹, Liu Chen¹, Yanlian Li¹, Danyan Cao¹, Xin Wang¹, Lin Chen¹, Jian Li¹, Tao Meng¹, Min Huang³, Meiyu Geng², Jingkang Shen¹, Naixia Zhang⁴, Bing Xiong⁵

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.

MeSH terms

Cell Line, Tumor
Cell Membrane / metabolism
Drug Discovery*
Humans
Neoplasms / drug therapy
Phosphodiesterase Inhibitors / pharmacology*
Phosphoric Diester Hydrolases / metabolism*
Protein Binding / drug effects*
Signal Transduction / drug effects
Triazoles / pharmacology
Triazoles / therapeutic use*
ras Proteins / metabolism*

Substances

Phosphodiesterase Inhibitors
Triazoles
Phosphoric Diester Hydrolases
ras Proteins