Patent number 8618106 is assigned to
The following quote was obtained by the news editors from the background information supplied by the inventors: "The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of intensive study is protein kinases.
"Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell (see, e.g., G.
"In general, protein kinases mediate intracellular signaling by affecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H.sub.2O.sub.2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a), and growth factors (e.g., granulocyte macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, survival and regulation of the cell cycle.
"Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, cancer, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
"The Polo-like kinases (PLKs) belong to a family of serine/threonine kinases that are highly conserved across the species, ranging from yeast to man (reviewed in Lowery D M et al., Oncogene, 2005, 24, 248-259). The PLKs have multiple roles in cell cycle, including control of entry into and progression through mitosis.
"PLK1 is the best characterized of the PLK family members. PLK1 is widely expressed and is most abundant in tissues with a high mitotic index. Protein levels of PLK1 rise and peak in mitosis (see, e.g.,
"PLK2 is mainly expressed during the G1 phase of the cell cycle and is localized to the centrosome in interphase cells. PLK2 knockout mice develop normally, are fertile and have normal survival rates, but are around 20% smaller than wild type mice. Cells from knockout animals progress through the cell cycle more slowly than in normal mice (see, e.g., S. Ma et al., Mol. Cell. Biol., 2003, 23, 6936-6943). Depletion of PLK2 by siRNA or transfection of kinase inactive mutants into cells blocks centriole duplication. Down-regulation of PLK2 also sensitizes tumor cells to taxol and promotes mitotic catastrophe, in part by suppression of the p53 response (see, e.g.,
"PLK3 is expressed throughout the cell cycle and increases from G1 to mitosis. Expression is up-regulated in highly proliferating ovarian tumors and breast cancer and is associated with a worse prognosis (see, e.g., W.
"PLK4 is structurally more diverse from the other PLK family members. Depletion of this kinase causes apoptosis in cancer cells (see, e.g.,
"Molecules of the protein kinase family have been implicated in tumor cell growth, proliferation and survival. Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. The evidence implicating the PLK kinases as essential for cell division is strong. Blockade of the cell cycle is a clinically validated approach to inhibiting tumor cell proliferation and viability. It would therefore be desirable to develop compounds that are useful as inhibitors of the PLK family of protein kinases (e.g., PLK1, PLK2, PLK3 and PLK4), that would inhibit proliferation and reduce viability of tumor cells, particularly as there is a strong medical need to develop new treatments for cancer, including treatments that would be administered orally."
In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "In one aspect, the present invention provides compounds of Formula I shown and described herein, as well as their pharmaceutically acceptable salts.
"The compounds of this invention in general are potent inhibitors of protein kinases, such as PLKs (polo-like kinases), e.g., PLK1, PLK2, PLK3, or PLK4. Accordingly, these compounds and their pharmaceutically acceptable salts and compositions are useful for treating or preventing diseases, disorders, or medical conditions implicated or mediated by protein kinases such as PLKs (polo-like kinases), e.g., PLK1, PLK2, PLK3, or PLK4. Examples of such diseases or conditions include cancers, e.g., melanoma, myeloma, leukemia, lymphoma, neuroblastoma, colon cancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer, lung cancer, central nervous system cancer, renal cancer, prostate cancer, bladder cancer, or pancreatic cancer.
"The compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors."
URL and more information on this patent, see: Charrier, Jean-Damien; Durrant, Steve. Protein Kinase Inhibitors. U.S. Patent Number 8618106, filed
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