Tomassi Stefano, Pfahler Julian, Mautone Nicola, Rovere Annarita, Esposito Chiara, Passeri Daniela, Pellicciari Roberto, Novellino Ettore, Pannek Martin, Steegborn Clemens, Paiardini Alessandro, Mai Antonello, Rotili Dante
Department of Pharmacy, University of Naples, "Federico II", 80131 Naples, Italy.
Department of Biochemistry and Research Center for Bio-Macromolecules, University of Bayreuth, 95440 Bayreuth, Germany.
ACS Med Chem Lett. 2020 Feb 3;11(5):862-868. doi: 10.1021/acsmedchemlett.9b00654. eCollection 2020 May 14.
Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.
端锚聚合酶（TNKSs）最近作为Wnt/β-连环蛋白信号通路依赖性实体瘤的潜在靶点受到了广泛关注。此前，我们报道了2-巯基喹唑啉-4-酮MC2050作为一种微摩尔级别的PARP1抑制剂。在此，我们展示了PARP1与MC2050复合物的X射线结构解析，结合对TNKSs与PARP1/2活性位点结构差异的计算研究，为基于结构的药物设计提供了理论依据。通过有限的合成工作，发现了双喹唑啉酮作为一种皮摩尔级别的选择性TNKS2抑制剂，在Wnt信号通路持续激活的结肠癌细胞系（DLD-1）中具有抗增殖作用。
