Ganji Santhi, Zou Jiwen, Brown Brock, Bobkova Ekaterina V., Ardecky Robert, Rosenstein Craig, Pass Ian, Dahl Russell, Vasile Stefan, Sergienko Eduard, Shi Shenghua, Stonich Derek, Cheltov Anton, Su Ying, Mangravita-Novo Arianna, Vicchiarelli Michael, McAnally Danielle, Kim Sylvia, Nguyen Hung, Moreira Tina Kiffer, Smith Layton H., Zeng Fu-Yue, Diwan Jena, Chung Thomas D.Y., Pinkerton Anthony B., Kaunitz Jonathan, Millán José Luis
Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
The isozymes of alkaline phosphatase (AP) are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates . Their localization in proximity to the cell surface suggests that they help facilitate the movement of substances across the plasma membrane. In humans, four isozymes of APs have been identified - one tissue-nonspecific (TNAP) and three tissue-specific isozymes named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) alkaline phosphatases. This project sought to identify isozyme and species selective inhibitors and activators of the human and mouse alkaline phosphatases. Concurrent high throughput screening (HTS) campaigns of the NIH Molecular Libraries Small Molecule Repository (MLSMR) library comprising ~355,000 compounds were completed against murine IAP (muIAP), human IAP (huIAP), TNAP and PLAP () were completed. This Center Probe Report describes the screens and structure activity relationship (SAR) elucidation that led to identification of a potent (540 nM IC) inhibitor of the murine IAP (muIAP), with 65-fold selectivity against TNAP and >185-fold selectivity against PLAP as well as the human isoform of IAP (huIAP).
碱性磷酸酶（AP）的同工酶能够使多种底物发生去磷酸化和转磷酸化反应。它们定位于细胞表面附近，这表明它们有助于促进物质跨质膜的移动。在人类中，已鉴定出四种AP同工酶——一种组织非特异性同工酶（TNAP）和三种根据其主要表达组织命名的组织特异性同工酶：肠道碱性磷酸酶（IAP）、胎盘碱性磷酸酶（PLAP）和生殖细胞碱性磷酸酶（GCAP）。该项目旨在鉴定人和小鼠碱性磷酸酶的同工酶及物种选择性抑制剂和激活剂。针对包含约355,000种化合物的美国国立卫生研究院分子文库小分子储存库（MLSMR）文库，同时开展了针对小鼠IAP（muIAP）、人IAP（huIAP）、TNAP和PLAP的高通量筛选（HTS）活动。本中心探针报告描述了筛选过程以及结构活性关系（SAR）的阐明，这些工作导致鉴定出一种对小鼠IAP（muIAP）有强效抑制作用（IC为540 nM）的抑制剂，对TNAP的选择性为65倍，对PLAP以及人IAP同工酶（huIAP）的选择性大于185倍。
