Abstract
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 micromol/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.
Highlights
In virtually all tumors, gene amplifications and/or deletions or functional alterations of key regulators contrive to deregulate the cyclin D1-cyclin-dependent kinase 4/p16/ pRb/E2F signaling axis [1] and, in the case of p27 and cyclin E, have prognostic value [2, 3]
Despite the lack of selective cdk1 inhibitors being described, dual cdk1-cdk2 inhibitors have been reported [12,13,14] and combined depletion of cdk1 and cdk2 is more proapoptotic than depletion of either cdk alone [9]. cdk1 has the attraction that it can regulate the activity of survivin (BIRC5), which has been implicated in regulation of the spindle checkpoint and inhibition of apoptosis and is selectively expressed in the majority of human tumor types [15]
AZD5438 was more potent against cdk2 and cdk1 than other drugs in the class, flavopiridol and R-roscovitine (Table 1)
Summary
Gene amplifications and/or deletions or functional alterations of key regulators contrive to deregulate the cyclin D1-cyclin-dependent kinase (cdk) 4/p16/ pRb/E2F signaling axis [1] and, in the case of p27 and cyclin E, have prognostic value [2, 3]. These observations have placed cdks among the most highly attractive targets for therapeutic intervention in cancer [4]. Inhibition of cdk rapidly down-regulates survivin expression-inducing MYCdependent apoptosis, leading to the suggestion that cdk inhibition might be a useful therapy for tumors that overexpress MYC, for example, in Burkitt's lymphoma [16]. cdk and cdk play roles in transcriptional regulation through
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