Discovery of DB18, a potent inhibitor of CLK kinases with a high selectivity against DYRK1A kinase

We describe in this paper the synthesis of a novel series anilino-2-quinazoline derivatives. These compounds have been screened against panel eight mammalian kinases and parallel they were tested for cytotoxicity on representative seven cancer cell lines. One them (DB18) has found to be very potent inhibitor human “CDC2-like kinases” CLK1, CLK2 CLK4, with IC50 values 10–30 nM range. Interestingly, molecule is inactive at 100 μM closely related “dual-specificity tyrosine-regulated kinase 1A” (DYRK1A). Extensive molecular simulation studies performed relevant explain strong affinity CLKs, as well its selectivity DYRK1A.