CP-724714 - CAS 383432-38-0
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Not Intended for Therapeutic Use. For research use only.
CP-724714 is An orally bioavailable quinazoline with potential antineoplastic activity. CP-724,714 selectively binds to the intracellular domain of HER2, reversibly inhibiting its tyrosine kinase activity and resulting in suppression of tumor cell growth. HER2, a member of the epidermal growth factor receptor (EGFR) family, is overexpressed in many adenocarcinomas, particularly breast cancers.
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OSI Pharmaceuticals and Pfizer
1.Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714.
Feng B1, Xu JJ, Bi YA, Mireles R, Davidson R, Duignan DB, Campbell S, Kostrubsky VE, Dunn MC, Smith AR, Wang HF. Toxicol Sci. 2009 Apr;108(2):492-500. doi: 10.1093/toxsci/kfp033. Epub 2009 Feb 17.
CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technology with mitochondria identified as a candidate organelle for its off-target toxicity. Additionally, CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approximately fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714.
2.Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor.
Jani JP1, Finn RS, Campbell M, Coleman KG, Connell RD, Currier N, Emerson EO, Floyd E, Harriman S, Kath JC, Morris J, Moyer JD, Pustilnik LR, Rafidi K, Ralston S, Rossi AM, Steyn SJ, Wagner L, Winter SM, Bhattacharya SK. Cancer Res. 2007 Oct 15;67(20):9887-93.
Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.
3.Pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors: correlations with clinical characteristics and safety.
Guo F1, Letrent SP, Munster PN, Britten CD, Gelmon K, Tolcher AW, Sharma A. Cancer Chemother Pharmacol. 2008 Jun;62(1):97-109. Epub 2007 Sep 6.
PURPOSE: CP-724,714 is an orally available, small molecule, potent HER-2 tyrosine kinase inhibitor under development for the treatment of advanced HER2-overexpressing cancers. In this study, the influence of baseline clinical characteristics and pathophysiological variables on the pharmacokinetics (PK) of CP-724,714, and the correlation between PK exposure and safety were examined in patients treated in the First-in-Human trial. PK and safety were also simulated for a Phase 2 trial at the recommended Phase 2 dose (RP2D) to assess if the simulated PK exposures of CP-724,714 covered the preclinically predicted efficacious concentrations, and if the predicted incidence of hepatic toxicities (>or=CTC grade 3) was acceptable.
4.First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER2-expressing tumors.
Munster PN1, Britten CD, Mita M, Gelmon K, Minton SE, Moulder S, Slamon DJ, Guo F, Letrent SP, Denis L, Tolcher AW. Clin Cancer Res. 2007 Feb 15;13(4):1238-45.
PURPOSE: To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2.
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