ABSTRACT
Therapeutic strategies for the treatment of metastatic melanoma show encouraging results in the clinic; however, not all patients respond equally and tumor resistance still poses a challenge. To identify novel therapeutic targets for melanoma, we screened a panel of structurally diverse organometallic inhibitors against human-derived normal and melanoma cells. We observed that a compound that targets PIM kinases (a family of Ser/Thr kinases) preferentially inhibited melanoma cell proliferation, invasion, and viability in adherent and three-dimensional (3D) melanoma models. Assessment of tumor tissue from melanoma patients showed that PIM kinases are expressed in pre- and post-treatment tumors, suggesting PIM kinases as promising targets in the clinic. Using knockdown studies, we showed that PIM1 contributes to melanoma cell proliferation and tumor growth in vivo; however, the presence of PIM2 and PIM3 could also influence the outcome. The inhibition of all PIM isoforms using SGI-1776 (a clinically-available PIM inhibitor) reduced melanoma proliferation and survival in preclinical models of melanoma. This was potentiated in the presence of the BRAF inhibitor PLX4720 and in the presence of PI3K inhibitors. Our findings suggest that PIM inhibitors provide promising additions to the targeted therapies available to melanoma patients.
Subject(s)
Imidazoles/pharmacology , Melanoma/drug therapy , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyridazines/pharmacology , Xenograft Model Antitumor Assays , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Gene Expression Profiling/methods , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Imidazoles/administration & dosage , Indoles/administration & dosage , Indoles/pharmacology , Melanoma/genetics , Melanoma/metabolism , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/genetics , Proto-Oncogene Proteins c-pim-1/metabolism , Pyridazines/administration & dosage , Pyrimidinones/administration & dosage , Pyrimidinones/pharmacology , RNA Interference , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Tumor Burden/drug effects , Tumor Burden/genetics , ortho-Aminobenzoates/administration & dosage , ortho-Aminobenzoates/pharmacologyABSTRACT
Octahedral metal complexes are attractive structural templates for the design of enzyme inhibitors as has been demonstrated, for example, with the development of metallo-pyridocarbazoles as protein kinase inhibitors. The octahedral coordination sphere provides untapped structural opportunities but at the same time poses the drawback of dealing with a large number of stereoisomers. In order to address this challenge of controlling the relative metal-centered configuration, the synthesis of rhodium(III) pyridocarbazole complexes with facially coordinating acyclic tridentate ligands was investigated. A strategy for the rapid synthesis of such complexes is reported, the diastereoselectivities of these reactions were investigated, the structure of several complexes were determined by X-ray crystallography, the high kinetic stability of such complexes in thiol-containing solutions was demonstrated in (1)H-NMR experiments, and the protein kinase inhibition ability of this class of complexes was confirmed. It can be concluded that the use of multidentate ligands is currently maybe the most practical strategy to avoid a large number of possible stereoisomers in the course of exploiting octahedral coordination spheres as structural templates for the design of bioactive molecules.
