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The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 111(35):E3689-98
- Publication Year :
- 2014
-
Abstract
- Nitrogen-containing heterocyclic compounds are an important class of molecules that are commonly used for the synthesis of candidate drugs. Phosphatidylinositol-4-phosphate 5-kinase-α (PIP5Kα) is a lipid kinase, similar to PI3K. However, the role of PIP5K1α in oncogenic processes and the development of inhibitors that selectively target PIP5K1α have not been reported. In the present study we report that overexpression of PIP5K1α is associated with poor prognosis in prostate cancer and correlates with an elevated level of the androgen receptor. Overexpression of PIP5K1α in PNT1A nonmalignant cells results in an increased AKT activity and an increased survival, as well as invasive malignant phenotype, whereas siRNA-mediated knockdown of PIP5K1α in aggressive PC-3 cells leads to a reduced AKT activity and an inhibition in tumor growth in xenograft mice. We further report a previously unidentified role for PIP5K1α as a druggable target for our newly developed compound ISA-2011B using a high-throughput KINOMEscan platform. ISA-2011B was discovered during our synthetic studies of C-1 indol-3-yl substituted 1,2,3,4-tetrahydroisoquinolines via a Pictet-Spengler approach. ISA-2011B significantly inhibits growth of tumor cells in xenograft mice, and we show that this is mediated by targeting PIP5K1α-associated PI3K/AKT and the downstream survival, proliferation, and invasion pathways. Further, siRNA-mediated knockdown of PIP5K1α exerts similar effects on PC3 cells as ISA-2011B treatment, significantly inhibiting AKT activity, increasing apoptosis and reducing invasion. Thus, PIP5K1α has high potential as a drug target, and compound ISA-2011B is interesting for further development of targeted cancer therapy.
- Subjects :
- Male
Indoles
Cell Survival
medicine.medical_treatment
Apoptosis
Diketopiperazines
Pharmacology
Biology
ta3111
Targeted therapy
Prostate cancer
Mice
Phosphatidylinositol 3-Kinases
Tetrahydroisoquinolines
Drug Discovery
medicine
Animals
Humans
Neoplasm Invasiveness
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Gene knockdown
Multidisciplinary
Cell growth
Prostatic Neoplasms
medicine.disease
Isoquinolines
ta3122
Xenograft Model Antitumor Assays
ta3123
Androgen receptor
Disease Models, Animal
Phosphotransferases (Alcohol Group Acceptor)
Signal transduction
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 10916490
- Volume :
- 111
- Issue :
- 35
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....286d28c440ffc9bbeba29ec5de17a5cc