Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
Bioorg Chem. 2020 Sep;102:104075. doi: 10.1016/j.bioorg.2020.104075. Epub 2020 Jul 8.
Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC = 12 μM), 4 (IC = 5.8 μM), and 10 (IC = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC = 0.082 μM) as the most potent inhibitor of PARP1 from the series.
聚（ADP-核糖）聚合酶 1（PARP1）是一种广泛研究的抗癌药物靶点，在单链 DNA 断裂修复过程中发挥重要作用。使用 PARP1-苯并咪唑-4-甲酰胺共晶结构和药效团模型对 Maybridge 小分子文库进行高通量虚拟筛选（HTVS），鉴定出 11 种化合物。这些化合物通过重组 PARP1 酶测定进行评估，得到了三种 PARP1 抑制剂：3（IC=12 μM）、4（IC=5.8 μM）和 10（IC=0.88 μM）。化合物 4（2,3-二氢-1,4-苯并二恶烷-5-甲酰胺）被选为先导化合物，并进行了进一步的化学修饰，包括类似物合成和支架跳跃。这些努力确定了（Z）-2-（4-羟基苄基）-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-8-甲酰胺（49，IC=0.082 μM）作为该系列中 PARP1 最强的抑制剂。
