ABSTRACT
There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.
Subject(s)
Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Imidazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Bone Neoplasms/enzymology , Bone Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Female , Humans , Immunohistochemistry , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/enzymology , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Osteoclasts/drug effects , Osteoclasts/pathology , Rats , Rats, Sprague-Dawley , Receptor, Macrophage Colony-Stimulating Factor/blood , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Substrate Specificity , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
Subject(s)
Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Lung/drug effects , Receptors, Interleukin-8B/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonic Acids/chemistry , Sulfonylurea Compounds/chemistry , Administration, Oral , Animals , Animals, Newborn , Biological Availability , Bronchoalveolar Lavage , Carboxylic Acids/pharmacokinetics , Chemotaxis/drug effects , Cytochrome P-450 Enzyme System/metabolism , Humans , Hyperoxia , Lung/metabolism , Lung Injury , Molecular Structure , Neutrophils/metabolism , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
