Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709

Siemeister, Gerhard; Luecking, Ulrich; Wagner, Christine; Detjen, Katharina; Coy, Catherine M.; Bosslet, Klaus

doi:10.1016/j.biopha.2006.06.003

Cited by 51 publications

(28 citation statements)

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“…5), (R)-roscovitine (CYC202/Seliciclib; refs. 11, 12), R547 (13,14), SNS-032 (15), PD-0332991 (16,17), AZD5438 (18,19), ZK 304709 (20,21), AG-024322, AT7519, and P276-00 (21).…”

Section: Introductionmentioning

confidence: 99%

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Bettayeb

Sallam

Ferandin

et al. 2008

Molecular Cancer Therapeutics

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“…5), (R)-roscovitine (CYC202/Seliciclib; refs. 11, 12), R547 (13,14), SNS-032 (15), PD-0332991 (16,17), AZD5438 (18,19), ZK 304709 (20,21), AG-024322, AT7519, and P276-00 (21).…”

Section: Introductionmentioning

confidence: 99%

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Bettayeb

Sallam

Ferandin

et al. 2008

Molecular Cancer Therapeutics

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“…drugs administered on a 3-week-treatment cycle, such as R547 or SCH 727965, have to overcome the hurdle to cover the whole length of the cell-division cycle at sufficient exposures (3,26). Another example is ZK 304709, an oral multitargeted CDK inhibitor, which showed a promising activity profile in various human tumor xenografts at high daily doses of up to 100 mg/kg (13,27). In phase I clinical trials, blood concentrations of ZK 304709 increased in a subdose proportional manner with high interpatient variability.…”

Section: Bay 1000394 Shows More Than Additive Efficacy In Combinationmentioning

confidence: 99%

“…Several low molecular weight inhibitors of CDKs with various inhibitor profiles on the panel of CDKs (9)(10)(11), some with additional non-CDK targets (12,13), have entered clinical trials (for recent review see ref.…”

Section: Introductionmentioning

confidence: 99%

BAY 1000394, a Novel Cyclin-Dependent Kinase Inhibitor, with Potent Antitumor Activity in Mono- and in Combination Treatment upon Oral Application

Siemeister

Lücking

Wengner

et al. 2012

Molecular Cancer Therapeutics

134

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Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC 50 values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials.

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“…In vitro, ZK 304709 was active at low levels with an inhibitory concentration 50% (IC 50 ) of 4 nM for CDK2/cyclinE and 30 nM for VEGFR-2 and PDGF-Rβ. In vivo, ZK 304709 was evaluated in more than 20 tumour xenograft models in nude mice with significant activity especially for breast, pancreatic, prostate, colorectal and renal cancer [6].…”

Section: Introductionmentioning

confidence: 99%

A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI™), in patients with advanced solid tumours

Scott

Thomas

Molife

et al. 2009

Cancer Chemother Pharmacol

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Purpose: The toxicities, pharmacokinetics and recommended dose of oral once-daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI™) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery.Methods: Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design.Results: Thirty-seven patients received ZK 304709 from 15 mg to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria. Conclusions:There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.3

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Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709

Cited by 51 publications

References 0 publications

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

BAY 1000394, a Novel Cyclin-Dependent Kinase Inhibitor, with Potent Antitumor Activity in Mono- and in Combination Treatment upon Oral Application

A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI™), in patients with advanced solid tumours

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