Evaluation of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of cdc2-like kinases (Clk)

Mott, Bryan T.; Tanega, Cordelle; Shen, Min; Maloney, David J.; Shinn, Paul; Leister, William; Marugán, Juan; Inglese, James; Austin, Christopher P.; Misteli, Tom; Auld, Douglas S.; Thomas, Craig J.

doi:10.1016/j.bmcl.2009.09.121

Cited by 66 publications

(80 citation statements)

References 29 publications

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“…For a broad coverage of chemical scaffolds, we compiled a series of compounds comprising known DYRK1A inhibitors (harmine [22], TG003 [24,25], KH-CB19 [26], 4,5,6,7-tetrabromobenzotriazole (TBB) [27,28]) and unspecific kinase inhibitors (staurosporin, curcumin). TBB was analysed because this compound had been used to establish the differential inhibitor sensitivity of the translational intermediate and mature form of dDYRK2 [13].…”

Section: Differential Effects Of Kinase Inhibitors On Autophosphorylamentioning

confidence: 99%

Mechanism of dual specificity kinase activity of DYRK1A

et al. 2013

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The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosinephosphorylation-regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non-catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co-translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin-dependent kinase-like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation. Structured digital abstract• CLK1 and CLK1 phosphorylate by protein kinase assay (View interaction)• HIPK2 and HIPK2 phosphorylate by protein kinase assay (View interaction)• DYRK1A phosphorylates SF3B1 by protein kinase assay (View interaction)• DYRK1A and DYRK1A phosphorylate by protein kinase assay (View interaction)

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Section: Differential Effects Of Kinase Inhibitors On Autophosphorylamentioning

confidence: 99%

Mechanism of dual specificity kinase activity of DYRK1A

et al. 2013

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“…Quinazoline derivatives display a large panel of activities, including kinase inhibition. For instance, 6-arylquinazolines are potent inhibitors of CDC2-like kinases [6], and pyrazolo [4,3-h]quinazoline-3-carboxamides have been developed as antitumor agents targeting multi-cyclin-dependent kinases and act as potent MPS1 kinase inhibitor [7]. Closely related structures such as harmine [8] or pyrazolo [3,4-b]pyridine [9] show significant activities of DYRK1A and CDK5-GSK3 inhibitors, respectively.…”

Section: Introductionmentioning

confidence: 98%

Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors

et al. 2012

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A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.

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“…31,32 The 1,352 member library contains several hundred analogs around each scaffold to provide dense structure-activity relationships (SAR) for active scaffolds. 27,33 In addition, we had previously determined that a quinazoline inhibitor was active at Clk4 34 and therefore we suspected that this library would provide a large set of active compounds to compare potency values between the 2 assay formats.…”

Section: Principle Of the Bioluminescent Assaysmentioning

confidence: 99%