Protein kinases as targets for anticancer agents: from inhibitors to useful drugs

Fabbro, Doriano; Ruetz, Stephan; Buchdunger, Elisabeth; Cowan‐Jacob, Sandra W.; Fendrich, Gabriele; Liebetanz, Janis; Mestan, Jürgen; O’Reilly, Terence; Traxler, Peter; Chaudhuri, Bhabatosh; Fretz, Heinz; Zimmermann, J.; Meyer, Thomas; Caravatti, Giorgio; Furet, Pascal; Manley, Paul W.

doi:10.1016/s0163-7258(02)00179-1

Cited by 309 publications

(188 citation statements)

References 101 publications

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“…The Plk1 kinase domain is an obvious target for drug development, and high-throughput screening and structure-based approaches used in the discovery and optimization of inhibitors of other protein kinases can be applied (Fabbro et al, 2002;Noble et al, 2004;Stout et al, 2004). The deep cavity of the ATP-binding pocket of kinases provides an excellent binding site for small molecules, and consequently the majority of available kinase inhibitors are ATP analogs.…”

Section: Prospects For Structure-based Drug Designmentioning

confidence: 99%

Structure and function of Polo-like kinases

2005

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Polo-like kinases play critical roles during multiple stages of cell cycle progression. All Polo-like kinases contain an N-terminal Ser/Thr kinase catalytic domain and a Cterminal region that contains one or two Polo-boxes. For Polo-like kinase 1, 2, and 3, and their homologs, the entire C-terminal region, including both Polo-boxes, functions as a single modular phosphoserine/threonine-binding domain known as the Polo-box domain (PBD). In the absence of a bound substrate, the PBD inhibits the basal activity of the kinase domain. Phosphorylation-dependent binding of the PBD to its ligands releases the kinase domain, while simultaneously localizing Polo-like kinases to specific subcellular structures. These observations suggest two different models for how the PBD integrates signals arising from other mitotic kinases to target the activated kinase towards distinct substrates. The recent X-ray crystal structures of the PBD provide insights into the structural basis for PBD function and kinase regulation. Molecular modelling of the structure of the isolated kinase domain reveals a potential basis for motif-dependent substrate specificity.

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Section: Prospects For Structure-based Drug Designmentioning

confidence: 99%

Structure and function of Polo-like kinases

2005

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“…Since the products of many oncogenes are PTKs and since defects in normal PTKs are closely associated with carcinogenesis, increasing numbers of inhibitors of PTKs have been developed as potential anticancer drugs (2)(3)(4)(5)(6)(7)(8). Examples of the most useful anticancer drugs available to date are STI571 (Gleevec), which is used in the treatment of patients with chronic myelocytic leukemia (4,9), and ZD1839 (Iressa), which is used to treat non-small cell lung cancer (10).…”

Section: From the Laboratory Of Biological Chemistry School Of Pharmmentioning

confidence: 99%

Involvement of Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) in Apoptosis Induced by β-Hydroxyisovalerylshikonin

Masuda

Shima

Aiuchi

et al. 2004

Journal of Biological Chemistry

135

104

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“…Chemical Clamping and Efficient Substrate Phosphorylation-Through detailed kinetic studies, we have shown that the high catalytic efficiency of the protein compared with the peptide substrate does not rest in a tightly bound Npl3 molecule, 2 Several conclusions about the relative values of S burst and k cat /K m can be made depending on the rates of the steps in Scheme 3. For example, S burst will be equivalent to the expression for k cat /K m (k cat /K m ϭ S burst ϭ k 3 /K d ) if k 4 Ͼ k Ϫ3 and k Ϫ2 Ͼ k 3 (42), an outcome not observed in our studies (S burst ϭ 3 M Ϫ1 s Ϫ1 and k cat /K m ϭ 0.17 M Ϫ1 s Ϫ1 ).…”

Section: Npl3 Does Not Influence the Rate-limitingmentioning

confidence: 99%

“…serine, threonine, and tyrosine) in eukaryotic proteins controls numerous physiological responses essential for cell function. The enzymes that catalyze this modification, the protein kinases, have been studied for their critical role in complex signaling cascades and for their potential as valuable chemotherapeutic targets in proliferative diseases (1,2). Although much is known about the protein kinase family on the structural and functional levels (3)(4)(5)(6), less is known about the interactions of these enzymes with their physiological protein substrates.…”

mentioning

confidence: 99%

Chemical Clamping Allows for Efficient Phosphorylation of the RNA Carrier Protein Npl3

Aubol

Ungs

Lukasiewicz³

et al. 2004

Journal of Biological Chemistry

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Protein kinases phosphorylate the appropriate protein substrate by recognizing residues both proximal and distal to the site of phosphorylation. Although these distal contacts may provide excellent binding affinities (low K m values) through stabilization of the enzymesubstrate complex, these contacts could reduce catalytic turnover (decrease k cat ) through slow phosphoprotein release. To investigate how protein kinases can overcome this problem and maintain both high substrate affinities and high turnover rates, the phosphorylation of the yeast RNA transport protein Npl3 by its natural protein kinase, Sky1p, was evaluated. Sky1p bound and phosphorylated Npl3 with a K m that was 2 orders of magnitude lower than a short peptide mimic representing the phosphorylation site and only proximal determinants. Surprisingly, this extraordinary difference is not the result of high affinity Npl3 binding. Rather, Npl3 achieves a low K m through a rapid and favorable phosphoryl transfer step. This step serves as a chemical clamp that locks the protein substrate in the active site without unduly stabilizing the product phosphoprotein and slowing its release. The chemical clamping mechanism offers an efficient means whereby a protein kinase can simultaneously achieve both high turnover and good substrate binding properties.The phosphorylation of hydroxyl-containing amino acids (i.e. serine, threonine, and tyrosine) in eukaryotic proteins controls numerous physiological responses essential for cell function. The enzymes that catalyze this modification, the protein kinases, have been studied for their critical role in complex signaling cascades and for their potential as valuable chemotherapeutic targets in proliferative diseases (1, 2). Although much is known about the protein kinase family on the structural and functional levels (3-6), less is known about the interactions of these enzymes with their physiological protein substrates. Protein kinases recognize and phosphorylate short peptide segments (consensus sequences) of 4 -10 residues based on the known phosphorylation sequences of their targets (7-9). Although these short segments (consensus sequences) are minimal substrates, they do not provide all the binding energy offered by the full-length protein substrate. For instance, the catalytic efficiency of phosphorylating the protein substrate MAPKAP2 using p38 MAPK 1 is ϳ2 orders of magnitude higher than that for a 14-residue peptide based on the consensus sequence (10). In another example, Csk phosphorylates the protein substrate Lck Ͼ3 orders of magnitude more efficiently than a 9-residue peptide based on the phosphorylation site (11). Studies of this type support a model in which regions beyond the limited consensus sequence interact with the protein kinase scaffold and govern high efficiency protein phosphorylation.Although an x-ray structure for a protein kinase with a full-length protein substrate bound is currently unavailable, structural and functional studies are now beginning to reveal the nature of the interactin...

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Protein kinases as targets for anticancer agents: from inhibitors to useful drugs

Cited by 309 publications

References 101 publications

Structure and function of Polo-like kinases

Structure and function of Polo-like kinases

Involvement of Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) in Apoptosis Induced by β-Hydroxyisovalerylshikonin

Chemical Clamping Allows for Efficient Phosphorylation of the RNA Carrier Protein Npl3

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