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| 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
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| 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.
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| Overall design |
Analysis of gene expression changes in A549 cells after treatment with allosteric inhibitors targeting atypical PKCs.
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| 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 |
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| Platforms (1) |
| GPL13607 |
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Feature Number version) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA268361 |
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