| 1. |
- Johansson, Martin, et al.
(författare)
-
Cancer therapy : targeting cell cycle regulators
- 2008
-
Ingår i: Anti-cancer agents in medicinal chemistry. - : Bentham Science Publishers. - 1871-5206 .- 1875-5992. ; 8:7, s. 723-31
-
Forskningsöversikt (refereegranskat)abstract
- Cyclins and CDKs play critical roles in DNA synthesis and cell division. Alterations in their function may lead to the disruption of normal cell growth and apoptosis, and subsequently, result in carcinogenesis. Elevated levels of cyclins and CDKs are frequently observed in a wide range of different types of human cancers. Understanding of molecular mechanisms underlying the cell cycle effects in response to the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to chemotherapeutic agents. Despite the clinical applications of cell cycle specific chemotherapeutic agents, there is still an urgent need to develop novel drugs that can target multiple sites and pathways of the cell cycle while avoiding drug induced cytotoxicity. In this review article, we will summarize the development of novel agents that specifically target cell cycle pathways in human cancer. We will discuss drugs that can directly interfere with the mitotic process of tumor cells. Moreover, we tend to address the significance of using small molecule CDK inhibitors that are derived from natural products.
|
|
| 2. |
- Semenas, Julius, et al.
(författare)
-
The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer
- 2014
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3689-E3698
-
Tidskriftsartikel (refereegranskat)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.
|
|
