A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers

Camidge, D. Ross; Pemberton, M. N.; Growcott, Jim; Amakye, Dereck D.; Wilson, David M.; Swaisland, Helen; Forder, Cheryl; Wilkinson, Robert W.; Byth, Kate; Hughes, Andrew

doi:10.1007/s00280-006-0387-2

Cited by 21 publications

(25 citation statements)

References 17 publications

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“…In a phase i study in healthy volunteers, the drug was found to have a relatively short half-life of 1-3 hours 57,58 . Nevertheless, pd effects were demonstrated; the drug led to statistically significant reductions in the ratio phospho-pRb /total pRb detected at 1.5 hours post-dose, but the effect disappeared at 6 hours post-dose.…”

Section: Azd5438mentioning

confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

191

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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Section: Azd5438mentioning

confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

191

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“…The dose-limiting adverse events were nausea and vomiting (49). A further, previously reported phase I clinical study, in which the pharmacodynamic activity of AZD5438 was evaluated (23), showed that the ratio of phospho-pRb/ total pRb was significantly reduced 1.5 hours after 40 and 80 mg AZD5438 compared with placebo. No significant differences were noted at 6 hours after dosing, consistent with the plasma t 1/2 of 1 to 3 hours and the rapid reversibility of pRb phosphorylation previously seen on cessation of dosing in preclinical studies.…”

mentioning

confidence: 99%

“…Here, we describe, for the first time, the preclinical development of AZD5438, a novel orally bioavailable, cdk1, cdk2, and cdk9 inhibitor. AZD5438 caused growth inhibition in a range of human tumor xenografts and showed pharmacodynamic effects on cdk substrates both preclinically and in human volunteers (23).…”

Section: Introductionmentioning

confidence: 99%

“…5 This model was adapted and combined with early human pharmacokinetic data (see ref. 49) to predict pRb response in buccal samples from healthy volunteers in the pharmacodynamic study described above (23). The closeness of the prediction from the model to the observed data suggested similarities in biomarker response to pRb between human xenograft cells implanted in nude mice and human buccal cells in healthy volunteers.…”

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confidence: 99%

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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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“…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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A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers

Abstract: The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.

Cited by 21 publications

References 17 publications

Development of Cell-Cycle Inhibitors for Cancer Therapy

Development of Cell-Cycle Inhibitors for Cancer Therapy

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

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

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