Exploiting structural principles to design cyclin-dependent kinase inhibitors

Noble, M.E.M.; Barrett, Paul J.; Endicott, Jane; Johnson, L.N.; McDonnell, James M.; Robertson, Giles; Zawaira, A.

doi:10.1016/j.bbapap.2005.08.019

Cited by 28 publications

(20 citation statements)

References 56 publications

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“…The extension of the residence time by hydrophobic interactions within the hinge region/front pocket appears also to be rationalized in part by kinase dynamics descriptions such as the "hydrophobic spine" model (18,38). The core of the hydrophobic spine consists of four amino acids that are considered to build a hydrophobic network/spine allowing the kinase "breathing motion" between the N lobe and the C lobe to enable nucleotide binding and release (39). In the case of the CDK/cyclin family, this mechanism is modified as exemplified for the CDK2/CycA complex (38), which positions the CDK loop accurately for the active kinase conformation even in the absence of an activatory T-loop phosphorylation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of the CDK/cyclin family, this mechanism is modified as exemplified for the CDK2/CycA complex (38), which positions the CDK loop accurately for the active kinase conformation even in the absence of an activatory T-loop phosphorylation (Fig. S5B) (38,39). Only in compounds that additionally interact with the hinge region of CDK8 or even more efficiently with the CDK8 front pocket as "anchor point," the CDK8 T-loop/CycC interaction surface (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structure–kinetic relationship study of CDK8/CycC specific compounds

Schneider

Böttcher²,

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

136

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In contrast with the very well explored concept of structure-activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure-kinetic relationship. Here, we present a structure-kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket.kinetic profiling | structure-based drug design T he cyclin-dependent kinase 8/cyclin C (CDK8/CycC) complex is a potent oncogene (1-4), involved in transcription and regulation of transcriptional activity (5-10), linked to epigenetic processes (11), and regarded as an attractive drug target. The recent clinical success of the small molecule inhibitors sorafenib (BAY-43006, Bayer Pharma) and imatinib (STI-571, Novartis Pharma AG) has been attributed to their deep pocket binding mode (12). The "deep pocket" (13) is adjacent to the kinase ATP binding site and accessible in protein kinases by the rearrangement of the DFG motif (a short motif composed of the residues AspPhe-Gly near the N-terminal region of the activation loop) from the active (DFG-in) to the inactive state (DFG-out) (13,14). Binding of a type II compound to such a DFG-out conformation often includes slow binding kinetics (15) with a prolonged "residence time," which is defined as the period for which a target is occupied by a compound (16). Residence time is currently considered to be a key success factor for compound optimization during drug discovery and perhaps as important as the apparent affinity such as half-inhibitory concentration (IC 50 ) or dissociation constant (K d ) (16,17). Accordingly, residence time could be a key to providing enhanced potency in vivo (18) and a means to improve the correlation of in vitro and in vivo efficacy of drugs (19). Despite the increased acceptance of the need to understand binding kinetics, the interplay between compound-target interactions and binding kinetics is in general too complex and poorly understood to enable prediction of the essential dynamic properties. The impact of the combination of kinetic data of proteininhibitor interactions with crystallographic studies has been recognized with pioneer studies such as bovine trypsin in complex with the bovine pancreatic trypsin inhibitor (20). The concept of structure-activity relationships describing the interdependency between binding affinity and compound structure has been well explored in the l...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure–kinetic relationship study of CDK8/CycC specific compounds

Schneider

Böttcher²,

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

136

View full text Add to dashboard Cite

show abstract

“…Although specific inhibition of a protein kinase is highly desirable, it remains a challenging goal in drug design [31][32][33][34]. In the past decade, many ATP-competitive inhibitors of cell cycle control related CDKs have been suggested [32, [35][36][37][38][39] and several of them have progressed to clinical trials targeting diverse types of cancer.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations on the inhibition of Cyclin-Dependent Kinases 2 and 5 in the presence of activators

Zhang

Tan

Lim

et al. 2006

J Comput Aided Mol Des

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Interests in CDK2 and CDK5 have stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. Molecular dynamics (MD) simulations have not only become a viable approach to drug design because of advances in computer technology but are increasingly an integral part of drug discovery processes. It is common in MD simulations of inhibitor/CDK complexes to exclude the activator of the CDKs in the structural models to keep computational time tractable. In this paper, we present simulation results of CDK2 and CDK5 with roscovitine using models with and without their activators (cyclinA and p25). While p25 was found to induce slight changes in CDK5, the calculations support that cyclinA leads to significant conformational changes near the active site of CDK2. This suggests that detailed and structure-based inhibitor design targeted at these CDKs should employ activator-included models of the kinases. Comparisons between P/CDK2/cyclinA/roscovitine and CDK5/p25/roscovitine complexes reveal differences in the conformations of the glutamine around the active sites, which may be exploited to find highly selective inhibitors with respect to CDK2 and CDK5.

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“…importance. Chemical genetics shows that [14] numerous small molecules have a significant impact on diverse areas of biology [15][16][17], which is a powerful tool for screening drugs that target specific proteins indispensable to the survival or proliferation of cancer cells [16,18,19]. Therefore, the 'library' would help to find effective anti-tumor compounds.…”

Section: Mmpt-induced Caspase-dependent Apoptosis In H1792 Cellsmentioning

confidence: 99%

MMPT: a thiazolidin compound inhibits the growth of lung cancer H1792 cells via Fas-mediated and caspase-dependent apoptosis pathway

Zhao

Sun

et al. 2009

Invest New Drugs

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MMPT, a thiazolidin compound, was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. However, the related mechanism has yet not been revealed. In this study, we investigated the cellular and molecular events underlying the antitumor function of this compound in human lung adenocarcinoma H1792 cells, focusing on the early cytotoxic effect. Treatment of H1792 cancer cells with MMPT (0.1-100 microM for 24-72 h) resulted in a growth inhibition in a dose and time-dependent manner, determined by MTT assay. This effect was accompanied by apoptosis, evidenced by Nucleosome ELISA, H33258 stained assay, and Sub-G1 analysis. Our data showed that MMPT caused activation of caspase-3, caspase-6 and caspase-8, but not caspase-9. The finding that MMPT induced apoptosis through a membrane-mediated mechanism was supported by the up-regulated expression of Fas (CD95/APO-1), and Fas ligand. Overall, our results demonstrated that MMPT induced growth inhibition of H1792 cells through a Fas-mediated and caspase-dependent apoptosis pathway, which suggested that MMPT might be used as a Fas/FasL and caspases promoter to initiate lung cancer cell apoptosis.

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Exploiting structural principles to design cyclin-dependent kinase inhibitors

Cited by 28 publications

References 56 publications

Structure–kinetic relationship study of CDK8/CycC specific compounds

Structure–kinetic relationship study of CDK8/CycC specific compounds

Molecular dynamics simulations on the inhibition of Cyclin-Dependent Kinases 2 and 5 in the presence of activators

MMPT: a thiazolidin compound inhibits the growth of lung cancer H1792 cells via Fas-mediated and caspase-dependent apoptosis pathway

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