title: Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory cell differentiation.
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.
authors.affiliation: Department 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.
authors.forename: Santosh A
authors.initials: SA
authors.lastname: Khedkar
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.forename: Alan C
authors.initials: AC
authors.lastname: Rigby
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051765:Early Growth Response Transcription Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology
chemical_list: D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D054852:Small Molecule Libraries