Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory cell differentiation.
Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory cell differentiation.
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DOI：
10.1021/jm5018187
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发表时间：
2015-02-12
影响因子：
7.3
通讯作者：
Feinberg MW
中科院分区：
文献类型：
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作者：
Khedkar SA;Sun X;Rigby AC;Feinberg MW
Krüppel 样转录因子家族 (KLF) 构成 C2H2 型锌指蛋白的亚家族，具有不同的细胞类型表达模式，调节细胞生长和分化、激活或发育的功能。先前已证明 KLF10 能够严格调节 CD4+CD25+ T 调节细胞分化和功能的获得，这对于维持自我耐受、免疫抑制和肿瘤免疫监视具有重要作用。迄今为止，尚无 KLF10 的选择性药理学抑制剂。在此，我们报告了使用化学库的计算机辅助药物设计 (CADD) 筛选发现了抑制 KLF10-DNA 相互作用界面的一流小分子化合物。对 KLF10 第二个锌指中的“可成药”口袋的检查发现了三种小分子，#48、#48-15 和 #15-09，具有相似的支架和结合模式。这些小分子均抑制 KLF10-DNA 结合和转录活性、CD4+CD25− T 细胞向 CD4+CD25+ T 调节细胞的转化以及 KLF10 靶基因表达。总而言之，这些发现支持使用 CADD 与功能测定来识别靶向转录因子 KLF 亚家族成员以调节健康和疾病中生物功能的小分子的可行性。我们希望这些新化合物能够作为 KLF10 介导效应和 T 调节细胞生物学的有用机制探针。
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 2nd 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.