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Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory

Santosh A Khedkar1, Xinghui Sun, Alan C Rigby

  • 1Department of Medicine, Division of Molecular and Vascular Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center , 99 Brookline Avenue, RN-227, Boston, Massachusetts 02215, United States.

Journal of Medicinal Chemistry
|January 13, 2015
PubMed

Insights

Researchers discovered novel small molecules that inhibit Krüppel-like factor 10 (KLF10) DNA binding. These compounds offer potential therapeutic strategies for regulating T regulatory cell function in immune and disease contexts.

Area of Science:

  • Molecular Biology
  • Immunology
  • Drug Discovery

Background:

  • Krüppel-like factors (KLFs) are transcription factors regulating cell growth and differentiation.
  • KLF10 is crucial for CD4+CD25+ T regulatory cell differentiation and function, impacting self-tolerance and immune suppression.
  • Currently, no selective pharmacological inhibitors exist for KLF10.

Purpose of the Study:

  • To discover the first-in-class small molecule inhibitors targeting the KLF10-DNA interaction.
  • To explore the potential of computer-aided drug design (CADD) for identifying inhibitors of KLF transcription factors.
  • To develop chemical probes for investigating KLF10-mediated biological processes.

Main Methods:

  • Computer-aided drug design (CADD) screening of chemical libraries.
  • Identification of small molecules binding to a druggable pocket in KLF10's zinc finger domain.
  • Functional assays to assess inhibition of KLF10-DNA binding, transcriptional activity, and T regulatory cell differentiation.

Main Results:

  • Three novel small molecules (#48, #48-15, #15-09) were identified that inhibit KLF10-DNA binding.
  • These compounds demonstrated efficacy in blocking KLF10's transcriptional activity.
  • Inhibition of KLF10 led to reduced conversion of CD4+CD25- T cells to CD4+CD25+ T regulatory cells.

Conclusions:

  • CADD combined with functional assays is a viable strategy for discovering inhibitors of KLF transcription factors.
  • The identified small molecules serve as valuable mechanistic probes for KLF10 and T regulatory cell biology.
  • These findings pave the way for developing targeted therapies modulating KLF family members for various diseases.

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