Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance

Willemsen-Seegers, Nicole; Uitdehaag, Joost C.M.; Prinsen, Martine B.W.; Vetter, Judith R.F. de; Man, Jos de; Sawa, Masaaki; Kawase, Yusuke; Buijsman, Rogier C.; Zaman, Guido J.R.

doi:10.1016/j.jmb.2016.12.019

Cited by 43 publications

(40 citation statements)

References 47 publications

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“…Second, a powerful and independent validation of the three-step binding mechanism is obtained by comparing the measured overall

of Danusertib with the calculated macroscopic

from the microscopic rate constants ( Figure 5G,H,I and Figure 5—figure supplement 1D ) according to Equation 4 , which indeed delivers values that are within experimental error. In addition, our values for

, and

are in good agreement with those reported in a recent study using SPR ( Willemsen-Seegers et al, 2017 ).…”

Section: Resultssupporting

confidence: 92%

Dynamics of human protein kinase Aurora A linked to drug selectivity

Pitsawong

Buosi

Otten

et al. 2018

eLife

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Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinase Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.

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“…Second, a powerful and independent validation of the three-step binding mechanism is obtained by comparing the measured overall

of Danusertib with the calculated macroscopic

, and

are in good agreement with those reported in a recent study using SPR ( Willemsen-Seegers et al, 2017 ).…”

Section: Resultssupporting

confidence: 92%

Dynamics of human protein kinase Aurora A linked to drug selectivity

Pitsawong

Buosi

Otten

et al. 2018

eLife

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“…[2] One of the first kinase inhibitors for which low dissociation rates have been described is the p38 inhibitor BIRB-796. [4] Indeed, more recent studies attributed the slow binding kinetics to efficient hydrophobic contacts rather than the kinetic dissociation barrier introduced by the DFG-out transition. [3] Inhibitors that bind to this conformation are called type II inhibitors and often have prolonged residence times (t).…”

mentioning

confidence: 99%

“…However,not all type II inhibitors show slow binding kinetics, suggesting that the DFG-out conformational change itself is not sufficient to explain the slow dissociation of BIRB-796. [4] Indeed, more recent studies attributed the slow binding kinetics to efficient hydrophobic contacts rather than the kinetic dissociation barrier introduced by the DFG-out transition. [5] However,c onformational change also contributes to the slow off-rate of the breast cancer drug lapatinib, at ype Ii nhibitor of the epidermal growth factor receptor.…”

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confidence: 99%

Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

et al. 2018

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Prolonged drug residence times may result in longer-lasting drug efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active-state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen-aromatic π interactions in the haspin-inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding-energy calculations.

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“…However, an examination of over 140,000 known kinase inhibitors indicated that kinase inhibitor promiscuity was the exception rather than the rule (Stumpfe, Tinivella, Rastelli, & Bajorath, 2017). In addition to determining IC 50/ K i values, kinase inhibitor selectivity can be further characterized by the assessment of inhibitor on-and off-rates and target residence time (see below; Willemsen-Seegers et al, 2017).…”

Section: Of 20mentioning

confidence: 99%

Reagent Validation to Facilitate Experimental Reproducibility

Williams

2018

CP Pharmacology

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Many results reported in the biomedical research literature cannot be independently reproduced, undermining the basic foundations of science. This overview is intended for researchers who are committed to improving the quality and integrity of biomedical science by raising awareness of both the sources of irreproducibility, and activities specifically targeted to address the issue. The irreproducibility of biomedical research is due to a variety of factors, known and unknown, that markedly influence experimental outcomes. Among the known factors are inadequate training or mentoring, or experimenter incompetence. These may result in flawed experimental design and execution that reflect a lack of planning, leading to an underpowering of a study, an absence of appropriate controls, selective data analysis, inappropriate statistical analysis, and/or investigator bias or fraud. Another frequently overlooked source of irreproducibility is failure to ensure that the equipment used is performing up to manufacturer specifications. Failure to validate/authenticate the experimental reagents is another source of irreproducibility. These include compounds, cell lines, antibodies, and the animal models used in a study. This overview discusses how a lack of validation of research reagents negatively impact experimental reproducibility, and provides guidelines to avoid these pitfalls. © 2018 by John Wiley & Sons, Inc.

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Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance

Cited by 43 publications

References 47 publications

Dynamics of human protein kinase Aurora A linked to drug selectivity

Dynamics of human protein kinase Aurora A linked to drug selectivity

Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

Reagent Validation to Facilitate Experimental Reproducibility

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