The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing

Jones, Clifford D.; Andrews, David M.; Barker, Andrew; Blades, Kevin; Daunt, Paula; East, Simon J.; Geh, Catherine; Graham, M. A.; Johnson, Keith M.; Loddick, Sarah A.; McFarland, Heather; McGregor, Alexandra; Moss, Louise; Rudge, David A.; Simpson, Peter B.; Swain, Michael L.; Tam, Kin Yip; Tucker, J.A.; Walker, Mike

doi:10.1016/j.bmcl.2008.10.102

Cited by 40 publications

(22 citation statements)

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“…To model the structural changes of the CDKA;1-F80G point mutation shown in Fig. 1b , the CDKA;1 sequence was used for NCBI-BLAST searches against PDB with default settings delivering five hits with the same scores and E-values (score = 419 E-value = 7e-118); PDB ID: 2W17 [ 72 ], 1FIN [ 73 ], 3EZR [ 74 ], 3PXF [ 75 ] and 1GZ8 [ 76 ]. We decided to use 1FIN as the modeling template since the other structures showed several disordered regions with missing side chains atoms or missing residues.…”

Section: Methodsmentioning

confidence: 99%

Modulation of plant growth in vivo and identification of kinase substrates using an analog-sensitive variant of CYCLIN-DEPENDENT KINASE A;1

et al. 2016

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BackgroundModulation of protein activity by phosphorylation through kinases and subsequent de-phosphorylation by phosphatases is one of the most prominent cellular control mechanisms. Thus, identification of kinase substrates is pivotal for the understanding of many – if not all – molecular biological processes. Equally, the possibility to deliberately tune kinase activity is of great value to analyze the biological process controlled by a particular kinase.ResultsHere we have applied a chemical genetic approach and generated an analog-sensitive version of CDKA;1, the central cell-cycle regulator in Arabidopsis and homolog of the yeast Cdc2/CDC28 kinases. This variant could largely rescue a cdka;1 mutant and is biochemically active, albeit less than the wild type. Applying bulky kinase inhibitors allowed the reduction of kinase activity in an organismic context in vivo and the modulation of plant growth. To isolate CDK substrates, we have adopted a two-dimensional differential gel electrophoresis strategy, and searched for proteins that showed mobility changes in fluorescently labeled extracts from plants expressing the analog-sensitive version of CDKA;1 with and without adding a bulky ATP variant. A pilot set of five proteins involved in a range of different processes could be confirmed in independent kinase assays to be phosphorylated by CDKA;1 approving the applicability of the here-developed method to identify substrates.ConclusionThe here presented generation of an analog-sensitive CDKA;1 version is functional and represent a novel tool to modulate kinase activity in vivo and identify kinase substrates. Our here performed pilot screen led to the identification of CDK targets that link cell proliferation control to sugar metabolism, proline proteolysis, and glucosinolate production providing a hint how cell proliferation and growth are integrated with plant development and physiology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-016-0900-7) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Modulation of plant growth in vivo and identification of kinase substrates using an analog-sensitive variant of CYCLIN-DEPENDENT KINASE A;1

et al. 2016

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“…In an effort to identify the best combination of Cdk activities that will lead to the greatest efficacy with minimal toxicity, several small molecules that inhibit the function of multiple Cdks with different relative potency are currently in phase I/II studies, in addition to flavopiridol, which is already in phase III clinical trials (26)(27)(28)(29)(30)(31)(32)(33)(34). Because many of these molecules are potent inhibitors of Cdk2 alone or in combination with Cdk4, the functional status of the Rb pathway can be used to assist in interpretation of clinical results with respect to target modulation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

Locatelli

Bosotti

Ciomei

et al. 2010

Molecular Cancer Therapeutics

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A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.

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“…Seventy-five structurally diverse CDK9 inhibitors were collected from published literatures [2,3,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The activities of these inhibitors were expressed as IC 50 values for CDK9 inhibition, which range from 2 to 30,000 nM.…”

Section: The Data Setmentioning

confidence: 99%

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

Fang

Xiao

Guo

2011

Journal of Molecular Graphics and Modelling

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The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing

Cited by 40 publications

References 10 publications

Modulation of plant growth in vivo and identification of kinase substrates using an analog-sensitive variant of CYCLIN-DEPENDENT KINASE A;1

Modulation of plant growth in vivo and identification of kinase substrates using an analog-sensitive variant of CYCLIN-DEPENDENT KINASE A;1

Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

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