digeranyl-bisphosphonate has been researched along with Multiple-Myeloma* in 2 studies
2 other study(ies) available for digeranyl-bisphosphonate and Multiple-Myeloma
| Article | Year |
|---|---|
Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors.
Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma. Topics: Apoptosis; Catalytic Domain; Cell Proliferation; Enzyme Inhibitors; Geranylgeranyl-Diphosphate Geranylgeranyltransferase; Humans; Inhibitory Concentration 50; Models, Molecular; Multiple Myeloma; Protein Prenylation; Pyrimidines; rap1 GTP-Binding Proteins | 2018 |
Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells.
Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines. Topics: Aminopyridines; Aniline Compounds; Antineoplastic Agents; Apoptosis; Catalytic Domain; Cell Survival; Crystallography, X-Ray; Diphosphonates; Drug Design; Extracellular Signal-Regulated MAP Kinases; Geranyltranstransferase; Hemiterpenes; Humans; Models, Molecular; Multiple Myeloma; Organophosphorus Compounds; Phosphorylation; Protein Conformation; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured | 2012 |