Imidazoles: SAR and development of a potent class of cyclin-dependent kinase inhibitors

Anderson, Malcolm; Andrews, David M.; Barker, Andy; Brassington, C.; Breed, J.; Byth, Kate; Culshaw, Janet D.; Finlay, M. Raymond V.; Fisher, Eric; McMiken, Helen; Green, Clive P.; Heaton, Dave W.; Nash, Ian A.; Newcombe, Nicholas J.; Oakes, Sandra; Pauptit, Richard A.; Roberts, Andrew; Stanway, J.; Thomas, Andrew P.; Tucker, J.A.; Walker, Mike; Weir, Hazel M.

doi:10.1016/j.bmcl.2008.09.024

Cited by 28 publications

(16 citation statements)

References 15 publications

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“…AZD5438 Is a Potent Inhibitor of cdks 1, 2, and 9 AZD5438 is a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine (24). Analytic evidence as well as an X-ray crystal structure of the compound bound to cdk2 confirmed the structure (Fig.…”

Section: Resultssupporting

confidence: 52%

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AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

Byth

Thomas

Hughes

et al. 2009

Molecular Cancer Therapeutics

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Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC 50 , 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC 50 range, 0.2-1.7 μmol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G 2 -M, S, and G 1 phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer 249 /Thr 252 , for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise.

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Section: Resultssupporting

confidence: 52%

“…Reagents AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, was synthesized by AstraZeneca Pharmaceuticals (24).…”

Section: Methodsmentioning

confidence: 99%

AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

Byth

Thomas

Hughes

et al. 2009

Molecular Cancer Therapeutics

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“…siRNA-mediated CDK2 silencing resulted in a significantly higher reduction in cell survival of cancer cells harbouring CCNE1 gene amplification than in cancer cells devoid of amplification of this gene (t-test, P < 0.05, Figures 5B, C). Furthermore, cancer cells harbouring CCNE1 gene amplification displayed a higher sensitivity to the CDK1, CDK2 and CDK9 small molecule inhibitor AZD5438 [56,57] than cancer cells lacking CCNE1 gene amplification (t-test, P = 0.019, Figure 5D). Moreover, primary breast cancers harbouring CCNE1 amplification were found to have higher levels of CDK2 mRNA expression, adjusted for proliferation using the mRNA levels of CCNB1 [58], than breast cancers devoid of CCNE1 amplification ( P = 0.02789, t-test, data not shown).…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of the 19q12 amplicon in grade III breast cancers

et al. 2012

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IntroductionThe 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.MethodsWe investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification.Results19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival.ConclusionsThe 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers.

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“…R-Roscovitine has demonstrated selective induction of apoptosis in cancer cells by down-regulation of anti-apoptotic proteins through transcriptional CDK inhibition [ 19 , 20 ]. Other CDK inhibitors, including AZD5438 [ 21 ], R547 [ 22 , 23 ] and AT519 [ 24 ], have also been evaluating in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73

et al. 2014

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Dysregulation of cellular transcription and translation is a fundamental hallmark of cancer. As CDK9 and Mnks play pivotal roles in the regulation of RNA transcription and protein synthesis, respectively, they are important targets for drug development. We herein report the cellular mechanism of a novel CDK9 inhibitor CDKI-73 in an ovarian cancer cell line (A2780). We also used shRNA-mediated CDK9 knockdown to investigate the importance of CDK9 in the maintenance of A2780 cells. This study revealed that CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. This subsequently caused a decrease in the eIF4E phosphorylation by blocking Mnk1 kinase activity. Consistently, CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis. The study confirmed that CDK9 is required for cell survival and that ovarian cancer may be susceptible to CDK9 inhibition strategy. The data also implied a role of CDK9 in eIF4E-mediated translational control, suggesting that CDK9 may have important implication in the Mnk-eIF4E axis, the key determinants of PI3K/Akt/mTOR- and Ras/Raf/MAPK-mediated tumorigenic activity. As such, CDK9 inhibitor drug candidate CDKI-73 should have a major impact on these pathways in human cancers.

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Imidazoles: SAR and development of a potent class of cyclin-dependent kinase inhibitors

Cited by 28 publications

References 15 publications

AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

Functional characterization of the 19q12 amplicon in grade III breast cancers

Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73

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