Manka Jason, Daniels Richard N., Dawson Eric, Daniels J. Scott, Southall Noel, Jadhav Ajit, Zheng Wei, Austin Chris, Grembecka Jolanta, Cierpicki Tomasz, Lindsley Craig W., Stauffer Shaun R.
Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center
NIH Chemical Genomics Center
A series of lead structures identified from a High Throughput Screen (HTS) targeting the Menin-Mixed Lineage Leukemia (MLL) protein-protein interaction are reported. Two chemical series have been prosecuted to date and one piperidine series was identified to have tractable and rapidly response Structure Activity Relationship (SAR) affording inhibitors of the Menin-MLL interaction with sub-micromolar inhibitory activity. Moreover, preliminary data suggests these compounds display activity in cellular systems relevant to understanding the Menin-MLL pathway and the disease progression. SAR and characterization of the declared probe ML227 from this effort are described.
报道了一系列从针对Menin-混合谱系白血病（MLL）蛋白质-蛋白质相互作用的高通量筛选（HTS）中鉴定出的先导结构。迄今为止，已对两个化学系列进行了研究，并且确定了一个哌啶系列具有易于处理且响应迅速的构效关系（SAR），可提供具有亚微摩尔抑制活性的Menin-MLL相互作用抑制剂。此外，初步数据表明这些化合物在与理解Menin-MLL途径和疾病进展相关的细胞系统中显示出活性。描述了此次研究中已申报的探针ML227的构效关系和表征。
