Llona-Minguez Sabin, Höglund Andreas, Wiita Elisee, Almlöf Ingrid, Mateus André, Calderón-Montaño José Manuel, Cazares-Körner Cindy, Homan Evert, Loseva Olga, Baranczewski Pawel, Jemth Ann-Sofie, Häggblad Maria, Martens Ulf, Lundgren Bo, Artursson Per, Lundbäck Thomas, Jenmalm Jensen Annika, Warpman Berglund Ulrika, Scobie Martin, Helleday Thomas
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University , 75123 Uppsala, Sweden.
J Med Chem. 2017 Mar 9;60(5):2148-2154. doi: 10.1021/acs.jmedchem.6b01786. Epub 2017 Feb 15.
The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit-to-lead development.
脱氧胞苷三磷酸焦磷酸酶1（dCTPase）参与细胞脱氧核苷酸三磷酸（dNTP）池的调节，并与癌症进展有关。在此，我们报告了一系列3,6-二取代的三唑并噻二唑作为强效dCTPase抑制剂的发现。化合物16和18在酶抑制和靶点结合之间表现出良好的相关性，同时在细胞协同模型中具有疗效，使其成为从苗头化合物到先导化合物开发的有希望的起点。
