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A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput
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A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput

Published on: September 22, 2019

Benzopyrazine derivatives: A novel class of growth factor receptor bound protein 7 antagonists

Nigus D Ambaye1, Menachem J Gunzburg, Reece C C Lim

  • 1Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Victoria 3800, Australia.

Bioorganic & Medicinal Chemistry
|December 8, 2010
PubMed

Insights

Researchers identified novel small molecule antagonists for Growth factor receptor bound protein 7 (Grb7), a protein implicated in various cancers. These Grb7 inhibitors show potential for reducing cancer cell growth and developing new cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Growth factor receptor bound protein 7 (Grb7) is a key adapter protein in growth factor signaling.
  • Overexpression of Grb7 is linked to multiple cancer types, including breast, blood, and gastric carcinomas.
  • Inhibiting Grb7 can decrease cancer cell migration and proliferation, highlighting its therapeutic potential.

Purpose of the Study:

  • To identify small molecule antagonists targeting the Grb7-SH2 domain.
  • To computationally design and experimentally validate novel Grb7 inhibitors.
  • To assess the therapeutic potential of identified compounds in cancer cell models.

Main Methods:

  • Utilized computational tools: ligand shape-based similarity search, molecular docking, and 2D-similarity search.
  • Screened the NCI chemical database for potential Grb7-SH2 domain binders.
  • Experimentally validated binding using melting point shift assays and isothermal titration calorimetry (ITC).

Main Results:

  • Identified 11 benzopyrazine-based small molecule antagonists with affinity for the Grb7-SH2 domain.
  • Compounds demonstrated moderate binding affinity in the low micromolar range via ITC.
  • The lead compound, NSC642056, inhibited Grb7-expressing breast cancer cell growth with an IC(50) of 86μM.

Conclusions:

  • Successfully identified novel small molecule antagonists for Grb7.
  • These compounds represent promising leads for further investigation into Grb7 function and therapeutic inhibition.
  • The identified antagonists could aid in developing new therapeutic strategies for Grb7-associated cancers.

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