Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation

  • Wen-Shan Liu
  • Wen-Yan Jin
  • Liang Zhou
  • Xing-Hua Lu
  • Wei-Ya Li
  • Ying MaEmail author
  • Run-Ling WangEmail author


SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migration and apoptosis. Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer. Hence, SHP2 has become a promising target for cancer immunotherapy. In this paper, we reported the identification of compound 1 as SHP2 inhibitor. Fragment-based ligand design, De novo design, ADMET and Molecular docking were performed to explore potential selective SHP2 allosteric inhibitors based on SHP836. The results of docking studies indicated that the selected compounds had higher selective SHP2 inhibition than existing inhibitors. Compound 1 was found to have a novel selectivity against SHP2 with an in vitro enzyme activity IC50 value of 9.97 μM. Fluorescence titration experiment confirmed that compound 1 directly bound to SHP2. Furthermore, the results of binding free energies demonstrated that electrostatic energy was the primary factor in elucidating the mechanism of SHP2 inhibition. Dynamic cross correlation studies also supported the results of docking and molecular dynamics simulation. This series of analyses provided important structural features for designing new selective SHP2 inhibitors as potential drugs and promising candidates for pre-clinical pharmacological investigations.


SHP2 Selective allosteric inhibitors De novo Molecular dynamics simulation 



Juvenile myelomonocytic leukemia


Myelodysplastic syndrome


Acute myeloid leukemia


T cell protein-tyrosine phosphatase


Protein tyrosine phosphatase 1B


SH2 domain-containing phosphatase 1

H bond

Hydrogen bond


Absorption, distribution, metabolism, excretion, and toxicity


Multi-copy simultaneous search


Fragment based drug design


Human intestinal absorption


Blood–brain barrier


Aqueous solubility plasma protein binding


Particle mesh Ewald


Molecular mechanics Poisson Boltzmann surface area


Linear combination of pairwise overlaps


Dynamic cross correlation


Molecular dynamics


High throughput virtual screening


Root mean square deviation


Root mean square fluctuation



This study was supported by the Natural Science Foundations of China (Grant No. 81273361), the Natural Science Foundation of Tianjin (Grant No. 16JCZDJC32500) and the International (Regional) Cooperation and Exchange Project of the National Natural Science Foundation of China (Grant No. 81611130090). The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No. 2017KJ229).

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest in this work.

Supplementary material

10822_2019_213_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 20 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of PharmacyTianjin Medical UniversityTianjinPeople’s Republic of China

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