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In this paper, we report a short and efficient synthesis of novel N -arylbenzo[ h ]quinazoline-2-amines. We have prepared a focused library of nineteen representative examples which have been submitted to cytotoxicity assays against a representative panel of eight cancer cell lines and several molecules gave attractive results in this area., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024, Veeraiah et al.)

Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g , with IC 50 = 0.004 µM in the inhibition of Hs CLK1 and IC 50 = 3.94 µM for the inhibition of Hs DYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18 , suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.

We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC 50 values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 μM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A., (Copyright © 2020 Elsevier Ltd. All rights reserved.)