Discovery of small molecule inhibitors to Krüppel-like factor 10 (klf10): Implications for modulation of t regulatory cell differentiation

Santosh A. Khedkar, Xinghui Sun, Alan C. Rigby, Mark W. Feinberg

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The Krüppel-like family of transcription factors (KLFs) constitute a subfamily of C2H2-type zinc finger proteins with distinct cell-type expression patterns and regulate functional aspects of cell growth and differentiation, activation, or development. KLF10 has been previously shown to critically regulate the acquisition of CD4+CD25+ T regulatory cell differentiation and function, an effect important to the maintenance of self-tolerance, immune suppression, and tumor immunosurveillance. To date, there are no selective pharmacological inhibitors to KLF10. Herein, we report on the discovery of first-in-class small molecule compounds that inhibit the KLF10-DNA interaction interface using computer-aided drug design (CADD) screens of chemical libraries. Interrogation of a "druggable" pocket in the second zinc finger of KLF10 revealed three small molecules, #48, #48-15, and #15-09, with similar scaffolds and binding patterns. Each of these small molecules inhibited KLF10-DNA binding and transcriptional activity, conversion of CD4+CD25- T cells to CD4+CD25+ T regulatory cells, and KLF10 target gene expression. Taken together, these findings support the feasibility of using CADD with functional assays to identify small molecules that target members of the KLF subfamily of transcription factors to regulate biological functions in health and disease. We hope these novel compounds will serve as useful mechanistic probes for KLF10-mediated effects and T regulatory cell biology.

Original languageEnglish (US)
Pages (from-to)1446-1478
Number of pages33
JournalJournal of Medicinal Chemistry
Volume58
Issue number3
DOIs
StatePublished - Feb 12 2015

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Computer-Aided Design
Cell Differentiation
Transcription Factors
Drug Design
Small Molecule Libraries
Self Tolerance
Immunologic Monitoring
DNA
Zinc Fingers
Regulatory T-Lymphocytes
Cell Biology
Pharmacology
T-Lymphocytes
Gene Expression
Health
Growth
Neoplasms
Proteins
CYS2-HIS2 Zinc Fingers

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of small molecule inhibitors to Krüppel-like factor 10 (klf10) : Implications for modulation of t regulatory cell differentiation. / Khedkar, Santosh A.; Sun, Xinghui; Rigby, Alan C.; Feinberg, Mark W.

In: Journal of Medicinal Chemistry, Vol. 58, No. 3, 12.02.2015, p. 1446-1478.

Research output: Contribution to journalArticle

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