The Department of Chemistry and Biochemistry, University of California, Santa Barbara 93106-9510, USA.
The Department of Chemistry and Biochemistry, University of California, Santa Barbara 93106-9510, USA; Molecular, Cellular and Developmental Biology, University of California, Santa Barbara 93106-9510, USA.
Bioorg Med Chem Lett. 2021 May 15;40:127908. doi: 10.1016/j.bmcl.2021.127908. Epub 2021 Mar 8.
Screening of a small chemical library (Medicines for Malaria Venture Pathogen Box) identified two structurally related pyrazolone (inhibitor 1) and pyridazine (inhibitor 2) DNMT3A inhibitors with low micromolar inhibition constants. The uncompetitive and mixed type inhibition patterns with DNA and AdoMet suggest these molecules act through an allosteric mechanism, and thus are unlikely to bind to the enzyme's active site. Unlike the clinically used mechanism based DNMT inhibitors such as decitabine or azacitidine that act via the enzyme active site, the inhibitors described here could lead to the development of more selective drugs. Both inhibitors show promising selectivity for DNMT3A in comparison to DNMT1 and bacterial DNA cytosine methyltransferases. With further study, this could form the basis of preferential targeting of de novo DNA methylation over maintenance DNA methylation.
从一个小型化学文库（疟疾药物 Venture 病原体盒）中筛选出两种结构相关的吡唑酮（抑制剂 1）和哒嗪（抑制剂 2）DNMT3A 抑制剂，其抑制常数低至微摩尔。与 DNA 和 AdoMet 的非竞争性和混合抑制模式表明这些分子通过变构机制起作用，因此不太可能与酶的活性位点结合。与通过酶活性位点起作用的临床使用的基于机制的 DNMT 抑制剂（如地西他滨或阿扎胞苷）不同，这里描述的抑制剂可能会导致更具选择性的药物的发展。与 DNMT1 和细菌 DNA 胞嘧啶甲基转移酶相比，这两种抑制剂对 DNMT3A 均显示出有希望的选择性。进一步研究，这可能为优先靶向从头 DNA 甲基化而不是维持 DNA 甲基化奠定基础。
