Davies, Barry R.;
Dudley, Philippa;
Cosulich, Sabina;
Luke, Richard;
Thompson, Neil;
Collins, Ian;
McHardy, Tatiana;
Garrett, Michelle;
Ogilvie, Donald
Abstract C208: CCT129254 (AT11854) is a well tolerated, orally bioavailable inhibitor of AKT/PKB with pharmacodynamic and antitumor activity in a range of xenograft models
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Medientyp:
E-Artikel
Titel:
Abstract C208: CCT129254 (AT11854) is a well tolerated, orally bioavailable inhibitor of AKT/PKB with pharmacodynamic and antitumor activity in a range of xenograft models
Beteiligte:
Davies, Barry R.;
Dudley, Philippa;
Cosulich, Sabina;
Luke, Richard;
Thompson, Neil;
Collins, Ian;
McHardy, Tatiana;
Garrett, Michelle;
Ogilvie, Donald
Erschienen:
American Association for Cancer Research (AACR), 2009
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>The PI3K/AKT/mTOR pathway is the most frequently deregulated pathway in human cancer. The serine/threonine kinase AKT (PKB), a member of the AGC family of protein kinases, is central to this pathway and is considered an important target for cancer therapy. However, the development of well tolerated, orally bioavailable inhibitors of catalysis targeting this enzyme has proved challenging and there are currently no such agents that have progressed to phase II clinical studies. We have characterised the pharmacodynamic and anti-tumor activity of CCT129254, a small molecule inhibitor of AKT. CCT129254 was well tolerated when dosed chronically at up to 200 mg/kg qd in nude mice. Acute doses of 100–200 mg/kg CCT129254 caused dose-dependent transient elevations of blood glucose concentration and inhibition of AKT substrate phosphorylation in xenografts. An acute dose of 200 mg/kg qd CCT129254 significantly reduced pGSK3 for &gt;6h in U87-MG xenografts, and this pharmacodynamic activity correlated with plasma drug concentration. Moreover, chronic dosing of CCT129254 caused a dose-dependent inhibition of tumor growth in this model. Chronic once daily dosing of CCT129254 significantly inhibited tumor growth in 14 of 16 other xenograft models, including breast, prostate, lung, ovarian, kidney and colon. The highest single agent activity was seen in two breast cancer xenografts (BT474c and HCC-1954). Significant activity was also seen in the gefitinib-resistant NCI-H1975 NSCLC model with respectively activating and resistance L858R and T790M mutations in EGFR. Increased efficacy is also seen when CCT129254 is combined with the cytotoxic agents cisplatin, doxorubicin and taxotere in xenograft models. CCT129254 exemplifies an oral, well tolerated inhibitor of AKT catalysis with the potential to inhibit the growth of a wide range of solid tumors both as monotherapy and in combination with cytotoxic agents.</jats:p>
<jats:p>Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C208.</jats:p>