title: The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer.
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.
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center.
authors: Julius
authors: J
authors: Semenas
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center.
authors: Andreas
authors: A
authors: Hedblom
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center.
authors: Regina R
authors: RR
authors: Miftakhova
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center.
authors: Martuza
authors: M
authors: Sarwar
authors: Center for Analysis and Synthesis, Lund University, 22100, Lund, Sweden; and.
authors: Rikard
authors: R
authors: Larsson
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center, Division of Neuroendocrine Cell Biology, Department of Clinical Science, Clinical Research Center, and.
authors: Liliya
authors: L
authors: Shcherbina
authors: Department of Laboratory Medicine, Lund University, 20502, Malmö, Sweden;
authors: Martin E
authors: ME
authors: Johansson
authors: Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, 20520 Turku, Finland.
authors: Pirkko
authors: P
authors: Härkönen
authors: Center for Analysis and Synthesis, Lund University, 22100, Lund, Sweden; and.
authors: Olov
authors: O
authors: Sterner
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center, jenny_l.persson@med.lu.se.
authors: Jenny L
authors: JL
authors: Persson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054659:Diketopiperazines / Q000494:pharmacology*; D004195:Disease Models, Animal; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D054659:Diketopiperazines; C000592937:ISA-2011B; D007211:Indoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: cancer metastasis; drug discovery; kinase inhibitor; targeted therapy