New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis

Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

“…The family of pyrido[3,4- g ]quinazoline-based compounds inhibiting CLK1, DYRK1A, CDK5, CK1, and GSK3 was published in 2019 [ 150 ]. More than 20 different analogs with varying selectivity were described in the report.…”

“…More than 20 different analogs with varying selectivity were described in the report. The most active compound towards CLK1 is the pyrido[3,4- g ]quinazoline 9m ( Figure 25 ), exhibiting IC 50 of 18 nM [ 150 ]. The inhibitory activities against DYRK1A, CDK5, CK1, and GSK3 were determined at fixed concentrations (10 µM and 1 µM); the residual kinase activities at 1µM concentration are: DYRK1A = 39%, CDK5 = 73%, CK1 = 98%, and GSK3 = 70%.…”

“…The inhibitory activities against DYRK1A, CDK5, CK1, and GSK3 were determined at fixed concentrations (10 µM and 1 µM); the residual kinase activities at 1µM concentration are: DYRK1A = 39%, CDK5 = 73%, CK1 = 98%, and GSK3 = 70%. However, more detailed information about the kinome-wide selectivity is not available [ 150 ].…”

5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency

“…Fused heteroaryl tricyclic scaffolds are among the most frequently reported Clk1 inhibitors, for example, those reported by Besson and co-workers [9], as well as those reported by the Moreau group and others [10][11][12]. Some of these tricyclic inhibitors display a significant growth inhibitory activity against various tumor cell lines; however, co-inhibition of related kinases besides Clk1 cannot be excluded, as selectivity data for some common off-targets are incomplete, e.g., regarding Dyrk1B, Dyrk2, haspin, CK2, STK17 and MLCK2 [13].…”

Synthesis and kinase inhibitory potencies of new pyrido[3,4-g]quinazolines substituted at the 8-position

“…For example, while analogues diversely substituted at 2-and 10-positions were active toward CLK1/DYRK1A, the introduction of alkyl/aryl groups at the 5-position was detrimental to the inhibition of CLK1/DYRK1A in favour of the one of CDK5/GSK3. [1][2][3][4] To complete this SAR study, we decided to focus our interest on the 8-position of the pyridoquinazoline scaffold (Figure 1), evaluating the impact of this structural modification on the biological activities. As previously reported, [1][2][3][4] the synthetic pathway was based on the preparation of a tetrasubstituted benzene derivative A, with substituents at the 1-and 2-positions used to construct the isoquinoline moiety (after Sonogashira cross-coupling with TMS-acetylene and subsequent cyclization in the presence of ammonia), while those at the 4-and 5-positions allowed the formation of the aminopyrimidine moiety (after oxidation, nitration and condensation with diversely substituted guanidine/amidine derivatives) (Scheme 1).…”