An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis

Discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors: synthesis, structure–activity relationship analysis and biological evaluation

“…All methyl esters (R 2 ¼ OCH 3 ), i.e., 6a (R 1 ¼ CH 3 in general structure I), 6b (R 1 ¼ CH 2 CH 2 OCH 3 ) and 12 (R 1 ¼ CH 3 in general structure II), are not active against both Mnk1 and Mnk2 with K i values being greater than 10 mM, and are moderately toxic against MV-4-11 cells with GI 50 values ranging from 13.44 to 47.82 mM. Both kinase inhibitory activity and cytotoxicity are consistent with the results previously obtained for methyl 4-(phenylamino)-5-methylthieno [2,3-d]pyrimidine-6-carboxylates [22]. Conversion of the methyl ester moiety into the carboxylic acid group resulting in 7a (R 1 ¼ CH 3 , R 2 ¼ OH in general structure I), 7b (R 1 ¼ CH 2 CH 2 OCH 3 , R 2 ¼ OH) and 13 (R 1 ¼ CH 3 , R 2 ¼ OH in general structure II), dramatically boosts the inhibitory activity against both Mnks, implying the involvement of the carboxylic acid in the interaction with the kinases.…”

“…A recent study demonstrated that the suppressive effects of cercosporamide on AML correlated with its Mnk inhibitory activity [24], supporting the potential application of pharmacologic Mnk inhibitors in anti-leukaemia therapy. As one of the most studied AML cell lines, MV-4-11 was selected for cell viability assay and cellular mechanistic investigation (vide infra) due to its increasing use for the assessment of anti-leukaemic effects of Mnk inhibition [18,24,25] as well as its sensitivity to Mnk inhibitors [18,22].…”

“…In the latter approach, CGP57380 and cercosporamide, two most extensively studied Mnk inhibitors, were selected as query molecules for the ligand-based alignment. Successful deployment of these two methods was followed by structure-guided optimisation and the evaluation of Mnk inhibitory activity of the remaining candidates using biochemical assays to reveal 4-aminothieno [2,3-d]pyrimidine as a valuable chemical scaffold for Mnk inhibitors [22]. Using analogue-based drug design, we further explored the utility and versatility of this scaffold.…”

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…The recently solved crystal structure of the mTOR kinase domain in complex with ATP-competitive inhibitor, PP242, will no doubt facilitate the design and synthesis of further catalytic mTOR inhibitors [108,109]. It is important to note that at this time there are no FDA approved drugs which specifically act on MNK kinases, and little progress has been made since the discovery of CGP57380, which exhibits low micromolar MNK inhibition [110]. Cercosporamide, a natural antifungal agent, was found to be a potent inhibitor of MNK1/2, in the nanomolar range.…”

“…However, its broad-spectrum . Screening data also showed no effect of MNKI-19 on CDK2A or CDK9T1 kinases [110]. Dual targeting of Mnks Review effects limit its uses as an effective treatment as it also inhibits a number of other kinases, including JAK3, GSK3β, ALK4 and Pim1 at low micromolar potency (see Figure 4) [9, 111,112].…”