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AZD5438 is 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. (source: Mol Cancer Ther. 2009 Jul;8(7):1856-66.)
Current developer: AstraZeneca
Phase I study of AZD-5438: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies (source: Ann Oncol. 2010 Apr;21(4):884-94.).
1: Boss DS, Schwartz GK, Middleton MR, Amakye DD,
Swaisland H, Midgley RS, Ranson M, Danson S, Calvert H, Plummer R,
Morris C, Carvajal RD, Chirieac LR, Schellens JH, Shapiro GI. Safety,
tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent
kinase inhibitor AZD5438 when administered at intermittent and
continuous dosing schedules in patients with advanced solid tumours. Ann
Oncol. 2010 Apr;21(4):884-94. Epub 2009 Oct 13. PubMed PMID: 19825886;
PubMed Central PMCID: PMC2844945.
(Keyword; CAS#; MedKoo code#)
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