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Series GSE63593 Query DataSets for GSE63593
Status Public on Jan 17, 2017
Title Gene expression profiling of A549 human lung cancer cell line treated with allosteric inhibitors targeting atypical PKCs
Organism Homo sapiens
Experiment type Expression profiling by array
Summary There is a current and ongoing need for improved cancer therapies. It is anticipated that future personalized cancer treatment will involve combinations of selective targeted drugs. A number of protein kinases, including members of the AGC group of kinases such as atypical protein kinase C (PKCi and PKCz) are validated drug targets. The regulation of many AGC protein kinases is mediated by a pocket in the small lobe of the kinase domain, the PIF-pocket. We developed a new compound class and provide biochemical and crystallography data showing that such compounds bind to the PIF-pocket and allosterically inhibit aPKC activity. We demonstrated that a representative compound, PS432, is a selective inhibitor in vivo. PS432, inhibited the proliferation of cancer cell lines more potently than ATM, a PKCi inhibitor in clinical trials, whereas PS432 had only minor effects on PNT1A cells. Analysis of the transcriptome by microarray and the proteome by SILAC indicated that the major effects of PS432 were on the cell cycle, while FACS indicated an accumulation of cells in the G1-G0 phase. PS432 significantly inhibited the growth of A549 tumor xenografts at 2.5 mg/kg/day without significant side effects. PS432 chemical class has good pharmacological properties and is orally available. Notably, PS432 had synergistic effects with a proteasome and with PI3-kinase inhibitors. The data indicates that derivatives from this new chemical class have potential for application in combination therapies in future personalized cancer treatments.
Overall design Analysis of gene expression changes in A549 cells after treatment with allosteric inhibitors targeting atypical PKCs.
Contributor(s) Arencibia JM, Biondi RM
Citation(s) 28045490
Submission date Nov 24, 2014
Last update date Nov 27, 2018
Contact name Jose M. Arencibia
Organization name Universitätsklinikum Frankfurt
Department Medizinische Klinik I
Lab Research Group PhosphoSites
Street address Theodor-Stern-Kai 7
City Frankfurt am Main
ZIP/Postal code 60590
Country Germany
Platforms (1)
GPL13607 Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Feature Number version)
Samples (16)
GSM1553320 A549_Untreated_0 hours
GSM1553321 A549_PS432 25 mM_4 hours
GSM1553322 A549_PS432 25 mM_8 hours
BioProject PRJNA268361

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
GSE63593_RAW.tar 199.1 Mb (http)(custom) TAR (of TXT)
GSE63593_median.txt.gz 73.3 Kb (ftp)(http) TXT
Processed data included within Sample table
Processed data provided as supplementary file
Processed data are available on Series record

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