دورية أكاديمية
AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity.
| العنوان: | AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity. |
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| المؤلفون: | Yap TA; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom., Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2012 Jul 15; Vol. 18 (14), pp. 3912-23. Date of Electronic Publication: 2012 Jul 10. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Neoplasms*/drug therapy , Neoplasms*/metabolism, Antineoplastic Agents/*administration & dosage , Phosphatidylinositol 3-Kinase/*metabolism , Protein Kinase Inhibitors/*administration & dosage, Apoptosis/drug effects ; Apoptosis/genetics ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation/drug effects ; Pyrimidines/administration & dosage ; Pyrroles/administration & dosage ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays |
| مستخلص: | Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. |
| معلومات مُعتمدة: | 11566 United Kingdom CRUK_ Cancer Research UK |
| المشرفين على المادة: | 0 (4-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-amine) 0 (Antineoplastic Agents) 0 (Phosphoinositide-3 Kinase Inhibitors) 0 (Protein Kinase Inhibitors) 0 (Pyrimidines) 0 (Pyrroles) EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) |
| تواريخ الأحداث: | Date Created: 20120712 Date Completed: 20130403 Latest Revision: 20211021 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1158/1078-0432.CCR-11-3313 |
| PMID: | 22781553 |
| قاعدة البيانات: | MEDLINE |
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