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Discovery of potent nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) inhibitors with ancillary carbonic anhydrase inhibition for cancer (immuno)therapy
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-6-16 , DOI: 10.1039/d1md00117e
Sang-Yong Lee 1 , Vigneshwaran Namasivayam 1 , Nader M Boshta 1, 2 , Arianna Perotti 1 , Salahuddin Mirza 1 , Silvia Bua 3 , Claudiu T Supuran 3 , Christa E Müller 1
Affiliation  

Nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) catalyzes the hydrolysis of extracellular nucleotides. It is expressed by immune cells and some carcinomas, e.g. of kidney and colon. Together with ecto-5′-nucleotidase (CD73), NPP3 produces immunosuppressive, cancer-promoting adenosine, and has therefore been proposed as a target for cancer therapy. Here we report on the discovery of 4-[(4-methylphthalazin-1-yl)amino]benzenesulfonamide (1) as an inhibitor of human NPP3 identified by compound library screening. Subsequent structure–activity relationship (SAR) studies led to the potent competitive NPP3 inhibitor 2-methyl-5-{4-[(4-sulfamoylphenyl)amino]phthalazin-1-yl}benzenesulfonamide (23, Ki 53.7 nM versus the natural substrate ATP). Docking studies predicted its binding pose and interactions. While 23 displayed high selectivity versus other ecto-nucleotidases, it showed ancillary inhibition of two proposed anti-cancer targets, the carbonic anhydrases CA-II (Ki 74.7 nM) and CA-IX (Ki 20.3 nM). Thus, 23 may act as multi-target anti-cancer drug. SARs for NPP3 were steeper than for CAs leading to the identification of potent dual CA-II/CA-IX (e.g. 34) as well as selective CA-IX inhibitors (e.g. 31).

中文翻译:

发现用于癌症(免疫)治疗的具有辅助碳酸酐酶抑制作用的强效核苷酸焦磷酸酶/磷酸二酯酶 3 (NPP3) 抑制剂

核苷酸焦磷酸酶/磷酸二酯酶 3 (NPP3) 催化细胞外核苷酸的水解。它由免疫细胞和一些癌(例如肾癌和结肠癌)表达。NPP3 与 ecto-5'-nucleotidase (CD73) 一起产生免疫抑制、促癌腺苷,因此已被提议作为癌症治疗的靶点。在这里,我们报告了 4-[(4-methylphthalazin-1-yl)amino]苯磺酰胺 ( 1 ) 作为通过化合物库筛选鉴定的人类 NPP3 抑制剂的发现。随后的构效关系 (SAR) 研究导致了有效的竞争性 NPP3 抑制剂 2-methyl-5-{4-[(4-sulfamoylphenyl)amino]phthalazin-1-yl}benzosulfonamide ( 23 , K i 53.7 nM天然底物 ATP 相比)。对接研究预测了它的结合姿势和相互作用。虽然23其他外核苷酸酶相比显示出高选择性,但它显示出对两种建议的抗癌靶点的辅助抑制作用,即碳酸酐酶 CA-II (K i 74.7 nM) 和 CA-IX (K i 20.3 nM)。因此,23可以作为多靶点抗癌药物。NPP3 的 SAR 比 CA 的陡峭,导致鉴定出有效的双重 CA-II/CA-IX(例如 34)以及选择性 CA-IX 抑制剂(例如 31)。
更新日期:2021-06-17
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