Lange Sandra, Hacker Stephan M, Schmid Philipp, Scheffner Martin, Marx Andreas
Department of Chemistry, Konstanz Research School-Chemical Biology, University of Konstanz, Universitätsstrasse 10, 78457, Konstanz, Germany.
Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Chembiochem. 2017 Sep 5;18(17):1707-1711. doi: 10.1002/cbic.201700226. Epub 2017 Jul 20.
The tumor suppressor Fhit and its substrate diadenosine triphosphate (Ap A) are important factors in cancer development and progression. Fhit has Ap A hydrolase activity and cleaves Ap A into adenosine monophosphate (AMP) and adenosine diphosphate (ADP); this is believed to terminate Fhit-mediated signaling. How the catalytic activity of Fhit is regulated and how the Fhit⋅Ap A complex might exert its growth-suppressive function remain to be discovered. Small-molecule inhibitors of the enzymatic activity of Fhit would provide valuable tools for the elucidation of its tumor-suppressive functions. Here we describe the development of a high-throughput screen for the identification of such small-molecule inhibitors of Fhit. Two clusters of inhibitors that decreased the activity of Fhit by at least 90 % were identified. Several derivatives were synthesized and exhibited in vitro IC values in the nanomolar range.
肿瘤抑制因子Fhit及其底物三磷酸二腺苷（ApA）是癌症发生和发展的重要因素。Fhit具有ApA水解酶活性，可将ApA裂解为单磷酸腺苷（AMP）和二磷酸腺苷（ADP）；据信这会终止Fhit介导的信号传导。Fhit的催化活性如何调节以及Fhit·ApA复合物如何发挥其生长抑制功能仍有待发现。Fhit酶活性的小分子抑制剂将为阐明其肿瘤抑制功能提供有价值的工具。在此，我们描述了一种用于鉴定此类Fhit小分子抑制剂的高通量筛选方法的开发。鉴定出了两组可使Fhit活性降低至少90%的抑制剂。合成了几种衍生物，其体外IC值在纳摩尔范围内。
