Senter Timothy, Gogliotti Rocco, Han Changho, Locuson Charles W., Morrison Ryan, Daniels J. Scott, Cierpicki Tomasz, Grembecka Jolanta, Lindsley Craig W., Stauffer Shaun R.
Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center
University of Michigan
A series of optimized Menin-Mixed Lineage Leukemia (MLL) protein-protein interaction inhibitors are reported leading to second generation probe ML399. HTS the Molecular Libraries Probe Production Centers Network (MLPCN) screening led to several chemotypes, including a piperidine class which successfully led to first generation probe ML227. Metabolic instability, potency, and ancillary pharmacology activity of ML227 were identified as limiting features. In order to enhance the utility of a menin-MLL inhibitor probe for in vivo proof-of-mechanism studies, a medicinal chemistry effort was reinitiated with a structure-based design approach incorporated. Novel menin-MLL inhibitors with improved potency and DMPK properties were identified leading to declared probe ML399. SAR and characterization of compounds within the series is described.
报道了一系列优化的Menin-混合谱系白血病（MLL）蛋白-蛋白相互作用抑制剂，从而产生了第二代探针ML399。分子文库探针生产中心网络（MLPCN）的高通量筛选产生了几种化学类型，包括一种哌啶类，该类成功产生了第一代探针ML227。ML227的代谢不稳定性、效力和辅助药理活性被确定为限制因素。为了提高用于体内机制验证研究的Menin-MLL抑制剂探针的效用，采用基于结构的设计方法重新启动了药物化学研究。鉴定出具有改善效力和药物代谢动力学性质的新型Menin-MLL抑制剂，从而产生了已申报的探针ML399。描述了该系列化合物的构效关系和特性。
