NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE38008 Query DataSets for GSE38008
Status Public on Jul 20, 2012
Title AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity
Organism Homo sapiens
Experiment type Expression profiling by array
Summary 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 demonstrated. 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 due to 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 demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial.
 
Overall design The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).
 
Contributor(s) Yap TA, Walton MI, Grimshaw KM, te Poele RH, Eve PD, Valenti M, De Haven Brandon A, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell R, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD
Citation(s) 22781553
Submission date May 16, 2012
Last update date Jan 23, 2019
Contact name Robert te Poele
E-mail(s) robert.te-poele@icr.ac.uk
Phone 00442087224319
Organization name The Institute of Cancer Research
Department Cancer Reserach UK Unit for Cancer Therapeutics
Lab Signal Transduction and Molecular Pharmacology Team
Street address 15 Cotswold Road
City Sutton
State/province Surrey
ZIP/Postal code SM2 5NG
Country United Kingdom
 
Platforms (1)
GPL6480 Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Probe Name version)
Samples (28)
GSM931782 U87MG_CCT128930_0.1µM_2
GSM931783 U87MG_AT13148_1xIC50_1
GSM931784 U87MG_DMSO_0_3
Relations
BioProject PRJNA167208

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE38008_RAW.tar 291.4 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap