Llona-Minguez S, Höglund A, Wiita E, Almlöf I, Mateus A, Calderón-Montaño JM, Cazares-Körner C, Homan E, Loseva O, Baranczewski P, Jemth AS, Häggblad M, Martens U, Lundgren B, Artursson P, Lundbäck T, Jenmalm Jensen A, Warpman Berglund U, Scobie M, Helleday T
J. Med. Chem. 60 (5) 2148-2154 [2017-03-09; online 2017-02-15]
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.
Biochemical and Cellular Screening