Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9

Ayaz, Pelin; Andres, Dorothee; Kwiatkowski, Dennis; Kolbe, Carl-Christian; Lienau, Philip; Siemeister, Gerhard; Lücking, Ulrich; Stegmann, C.

doi:10.1021/acschembio.6b00074

Cited by 62 publications

(55 citation statements)

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“…However, thermodynamic selectivity may not map with kinetic selectivity, and indeed as noted above, kinetic selectivity can still exist even in the absence of thermodynamic selectivity. 21,23,38−41 …”

Section: Kinetic Selectivitymentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

222

235

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The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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Section: Kinetic Selectivitymentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

222

235

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“…[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. [8] In some cases,t he presence of water-shielded hydrogen bonds can also lead to slow dissociation. [6] In addition to protein conformational changes,t he rearrangement of water molecules has been discussed as apotential mechanism influencing inhibitor residence time.…”

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confidence: 99%

“…[12] Ar ecent survey of the PDB archive for halogen-protein interactions reported that 33 %ofall non-bonded interactions (excluding C À X···H contacts) of the heavier halogens in the protein database form aromatic stacking interactions of the C À X···p type. strated for the CDK inhibitor roniciclib, [8] and it is likely that halogen atoms also contribute to the very slow off-rates observed for the ERK inhibitor VTX-11e. The effect of gatekeeper mutation on the binding kinetics of haspin with tubercidin derivatives.…”

mentioning

confidence: 99%

“…[7] An example for the influence of water molecules on ligand binding kinetics is the type ICDK inhibitor roniciclib,whose slow off-rate is the result of changes in the hydration network coupled to conformational adaptation of the DFG motif. [8] In some cases,t he presence of water-shielded hydrogen bonds can also lead to slow dissociation. [9] In addition, reversible covalent inhibitors provide an interesting strategy for prolonging target engagement by transient covalent-bond formation.…”

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confidence: 99%

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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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“…These results were in accordance with a sustained inhibitory effect on retinoblastoma protein phosphorylation, indicating that the target RT on CDK2 may contribute to sustained target engagement and antitumor efficacy. 9 Importantly, kinetic selectivity can only occur when a drug's RT outlasts its PK profile.…”

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confidence: 99%

The Added Value of Assessing Ligand–Receptor Binding Kinetics in Drug Discovery

Guo

Heitman

IJzerman

2016

ACS Med. Chem. Lett.

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In the past decade drug research community has started to appreciate the indispensable role of ligand−receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand−receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action. Translational models incorporating BK are emerging as well, which represent powerful tools for the prediction of in vivo effects. In this viewpoint we will summarize some recent findings and discuss and emphasize the added value of ligand−receptor binding kinetics in drug research.

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Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9

Cited by 62 publications

References 54 publications

Drug–Target Kinetics in Drug Discovery

Drug–Target Kinetics in Drug Discovery

Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

The Added Value of Assessing Ligand–Receptor Binding Kinetics in Drug Discovery

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