State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, No.2 Linggong Road, Dalian 116012, PR China.
Eur J Med Chem. 2013 Feb;60:410-20. doi: 10.1016/j.ejmech.2012.12.016. Epub 2012 Dec 17.
We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1.
我们之前曾报道过一种针对抗凋亡 Mcl-1 蛋白的纳摩尔抑制剂，3-硫代吗啉-8-氧代-8H-吖萘并[1,2-b]吡啶-9-甲腈（S1）。S1 通过与 Mcl-1 的 BH3 凹槽结合发挥作用。基于这一空间结构特征，我们采用基于片段的药物发现方法开发了一类新型的 Mcl-1 抑制剂。通过对 S1 进行剖析，我们确定了以 2-羟基吡啶核为起始片段的化合物 4。在接下来的分子生长过程中，我们使用配体效率评估和拟合质量评分来评估片段。我们得到了一种新型的强效化合物 N-苄基-5-(4-异丙基噻吩-2-基)-2-羟基烟酰胺（12c），其对 Mcl-1 的 IC50 值为 54 nM。化合物 12c 的水溶性优于 S1。
