Adenosine-5′-carboxylic acid peptidyl derivatives as inhibitors of protein kinases

Loog, Mart; Uri, Asko; Raidaru, Gerda; Järv, Jaak; Ek, Pia

doi:10.1016/s0960-894x(99)00210-3

Cited by 28 publications

(24 citation statements)

References 21 publications

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“…9). Variation of any of the aforementioned structural fragments results in changes of affinity and selectivity of ARCs towards their biological targets, as has been demonstrated in previous studies [34,36–38,51]. …”

Section: Discussionsupporting

confidence: 56%

Adenosine analogue–oligo-arginine conjugates (ARCs) serve as high-affinity inhibitors and fluorescence probes of type I cGMP-dependent protein kinase (PKGIα)

Lavõgina

Nickl

Enkvist

et al. 2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Introduction Type I cGMP-dependent protein kinase (PKGIα) belongs to the family of cyclic nucleotide-dependent protein kinases and is one of the main effectors of cGMP. PKGIα is involved in regulation of cardiac contractility, vasorelaxation, and blood pressure; hence, the development of potent modulators of PKGIα would lead to advances in the treatment of a variety of cardiovascular diseases. Aim Representatives of ARC-type compounds previously characterized as potent inhibitors and high-affinity fluorescent probes of PKA catalytic subunit (PKAc) were tested towards PKGIα to determine that ARCs could serve as activity regulators and sensors for the latter protein kinase both in vitro and in complex biological systems. Results Structure–activity profiling of ARCs with PKGIα in vitro demonstrated both similarities as well as differences to corresponding profiling with PKAc, whereas ARC-903 and ARC-668 revealed low nanomolar displacement constants and inhibition IC50 values with both cyclic nucleotide-dependent kinases. The ability of ARC-based fluorescent probes to penetrate cell plasma membrane was demonstrated in the smooth muscle tissue of rat cerebellum isolated arteries, and the compound with the highest affinity in vitro (ARC-903) showed also potential for in vivo applications, fully abolishing the PKG1α-induced vasodilation.

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Section: Discussionsupporting

confidence: 56%

Adenosine analogue–oligo-arginine conjugates (ARCs) serve as high-affinity inhibitors and fluorescence probes of type I cGMP-dependent protein kinase (PKGIα)

Lavõgina

Nickl

Enkvist

et al. 2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…However, the modularity of the BL was not known, that is could another ATP-cleft directed small molecule ligand replace staurosporine post-selection in the context of the optimized BL, 4 ? To address the modularity of the small molecule warhead, an adenosine derivative35 was substituted as the ATP-competitive ligand (Figure 4) conjugated to the cyclic peptide via the optimal 7 β-alanine linker, 6 . The IC 50 of the adenosine derived BL was found to be 2.9 µM, which is a >300-fold improvement from the adenosine derivative, 6a , (IC 50 > 1 mM).…”

Section: Resultsmentioning

confidence: 99%

Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA): Optimization and selectivity profiling

Shomin

Meyer

Ghosh

2009

Bioorganic & Medicinal Chemistry

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We have recently developed a fragment based selection strategy for targeting kinases, where a small molecule warhead can be non-covalently tethered to a phage-displayed library of peptides. This approach was applied to the conversion of the promiscuous kinase inhibitor, staurosporine, into a potent bivalent ligand for cAMP-dependent protein kinase (PKA). Herein we report a systematic evaluation of this new bivalent ligand (BL); (a) Lineweaver-Burke analysis revealed that the BL, unlike substrate-based bivalent kinase inhibitors, displayed non-competitive inhibition with respect to the peptide substrate, suggesting an allosteric mechanism of action; (b) linker optimization of the BL, afforded one of the most potent, sub-nanomolar, inhibitors of PKA reported to date; (c) the BL was found to be modular, where attachment of active site targeted small molecule warheads in lieu of staurosporine could achieve similar gains in affinity; and (d) profiling studies of both the staurosporine derivative and the BL (amide isostere) against a panel of 90 kinases revealed almost unique enhancement in selectivity against PKA (>5-fold) compared to the starting staurosporine derivative. These combined results provide new insights for BL discovery, which has the potential to provide guidance towards the development of kinase selective reagents while uncovering new allosteric sites on kinases for therapeutic targeting.

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“…These disadvantages have now been overcome by the incorporation of structural elements that improve cell penetration (e.g., transport peptides) [24,56] and proteolytic stability (e.g., peptidomimetic fragments) of the compounds. [11,12] The bisubstrate inhibitors can also be successfully applied in biochemical and biophysical methods where the restrictions valid for drugs (e.g., Lipinski's rule of five) [71] are not essential.…”

Section: Discussionmentioning

confidence: 99%

“…The compounds exhibited sub-micromolar affinity towards PKAc, PKC, and ROCK. [24,56] The oligo-arginine fragment possessing the transport peptide characteristics made the conjugates cell plasma-membrane permeable. [57,58] The development of the next generation of ARC-type inhibitors, ARC(II), included several structural modifications.…”

Section: Development Of Bisubstrate Inhibitors Of Pks: Arc-type Inhibmentioning

confidence: 99%

Bisubstrate Inhibitors of Protein Kinases: from Principle to Practical Applications

2009

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Bisubstrate inhibitors consist of two conjugated fragments, each targeted to a different binding site of a bisubstrate enzyme. The design of bisubstrate inhibitors presupposes the formation of the ternary complex in the course of the catalyzed reaction. The principle advantage of bisubstrate inhibitors is their ability to generate more interactions with the target enzyme that could result in improved affinity and selectivity of the conjugates, when compared with single-site inhibitors. Among phosphotransferases, the approach was first successfully used for adenylate kinase in 1973. Since then, several types of bisubstrate inhibitors have been developed for protein kinases, including conjugates of peptides with nucleotides, adenosine derivatives and potent ATP-competitive inhibitors. Earlier bisubstrate inhibitors had pharmacokinetic qualities that were unsuitable for cellular experiments and hence were mostly used for in vitro studies. The recently constructed conjugates of adenosine derivatives and D-arginine-rich peptides (ARCs) possess high kinase affinity, high biological and chemical stability and good cell plasma membrane penetrative properties that enable their application in the regulation of cellular protein phosphorylation balances in cell and tissue experiments.

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Adenosine-5′-carboxylic acid peptidyl derivatives as inhibitors of protein kinases

Cited by 28 publications

References 21 publications

Adenosine analogue–oligo-arginine conjugates (ARCs) serve as high-affinity inhibitors and fluorescence probes of type I cGMP-dependent protein kinase (PKGIα)

Adenosine analogue–oligo-arginine conjugates (ARCs) serve as high-affinity inhibitors and fluorescence probes of type I cGMP-dependent protein kinase (PKGIα)

Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA): Optimization and selectivity profiling

Bisubstrate Inhibitors of Protein Kinases: from Principle to Practical Applications

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