School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Future Med Chem. 2021 Aug;13(15):1253-1269. doi: 10.4155/fmc-2021-0088. Epub 2021 Jun 28.
STAT3 is a pro-oncogenic transcription factor. Pyrimethamine (PYM) is a STAT3 inhibitor that suppresses the proliferation of some cancer cells through downregulation of STAT3 target proteins. We have used structure-based tools to design novel PYM-based compounds. Intracellular target validation studies revealed that representative compounds and downregulate STAT3 downstream proteins and inhibit STAT3 DNA binding domain (DBD). Relative to PYM, a cohort of these compounds are >100-fold more cytotoxic to cancer cells with constitutively active (high pSTAT3) and basal (low pSTAT3) STAT3 signaling, suggesting that STAT3 DBD inhibition is deleterious to the proliferation of cancer cells with low and high pSTAT3 levels. These are promising leads for further preclinical evaluation as therapeutic agents for STAT3-dependent cancers.
STAT3 是一种致癌转录因子。嘧啶苯并咪唑（PYM）是一种 STAT3 抑制剂，通过下调 STAT3 靶蛋白来抑制一些癌细胞的增殖。我们已经使用基于结构的工具来设计新型 PYM 基化合物。细胞内靶标验证研究表明，代表性化合物和下调 STAT3 下游蛋白并抑制 STAT3 DNA 结合域（DBD）。与 PYM 相比，这些化合物中的一组对具有组成性激活（高 pSTAT3）和基础（低 pSTAT3）STAT3 信号的癌细胞的细胞毒性高 100 倍以上，这表明 STAT3 DBD 抑制对低和高 pSTAT3 水平的癌细胞的增殖是有害的。这些是作为 STAT3 依赖性癌症治疗剂进行进一步临床前评估的有希望的先导化合物。
