Strategies toward the Design of Novel and Selective Protein Tyrosine Kinase Inhibitors

Traxler, Peter; Furet, Pascal

doi:10.1016/s0163-7258(98)00044-8

Cited by 372 publications

(283 citation statements)

References 32 publications

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“…A further conserved aspartate residue in the catalytic domain may aid in the phosphate transfer by deprotonating the substrate hydroxyl group enabling it to more readily attack and remove the terminal phosphate from ATP [75]. The catalytic domain in the active conformation has been well characterised and an early pharmacophore model built to describe the ATP binding site has been successfully used for rational drug development [136] (Fig. 2).…”

Section: Protein Kinase Structure and Selective Inhibitionmentioning

confidence: 99%

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Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.

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Section: Protein Kinase Structure and Selective Inhibitionmentioning

confidence: 99%

“…On the other hand, as the ATP binding site structure of active kinases is so conserved throughout the class, it may be more difficult to gain specificity for a particular kinase. [136]. Grey shading indicates non-conserved regions.…”

Section: Protein Kinase Structure and Selective Inhibitionmentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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“…11,12 The relevance of EGFR expression in tumors to prognostic outcome supports the years of investment towards finding an EGFRtargeted therapeutic [13][14][15][16][17][18] and the need for a diagnostic imaging agent. Development of an imaging agent might also be a valuable tool in the search for and the characterization of EGFR-targeted therapeutics.…”

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confidence: 99%

Anilinodialkoxyquinazolines: Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

et al. 2005

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“…The binding modes for ATP and erlotinib are also consistent with the existing pharmacophore model for ATP binding to kinases. 66,67,74 Significantly, a second binding mode, which has a higher affinity to the mutant kinase L834R, is revealed in our calculations. This mode still blocks the ATP binding pocket and in addition shows an additional interaction between erloitnib and the R834 residue.…”

Section: Constitutive Activation Of the L834r Mutantmentioning

confidence: 52%

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

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Abstract-We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/ continuum stochastic dynamics protocols to study the dimermediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

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Strategies toward the Design of Novel and Selective Protein Tyrosine Kinase Inhibitors

Cited by 372 publications

References 32 publications

Measuring and interpreting the selectivity of protein kinase inhibitors

Measuring and interpreting the selectivity of protein kinase inhibitors

Anilinodialkoxyquinazolines: Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

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