JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia.

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.

• Authors: Carl L Manthey, Dana L Johnson, Carl R Illig, Robert W Tuman, Zhao Zhou, Judith F Baker, Margery A Chaikin, Robert R Donatelli, Carol F Franks, Lee Zeng, Carl Crysler, Yanmin Chen, Edward J Yurkow, Lisa Boczon, Sanath K Meegalla, Kenneth J Wilson, Mark J Wall, Jinsheng Chen, Shelley K Ballentine, Heidi Ott, Christian Baumann, Danielle Lawrence, Bruce E Tomczuk, Christopher J Molloy
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 11 Pg. 3151-61 (Nov 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19887542 (Publication Type: Journal Article)

Chemical References

• 4-cyano-N-(2-(1-cyclohexen-1-yl)-4-(1-((dimethylamino)acetyl)-4-piperidinyl)phenyl)-1H-imidazole-2-carboxamide
• Imidazoles
• Piperidines
• Protein Kinase Inhibitors
• Receptor, Macrophage Colony-Stimulating Factor
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Bone Neoplasms (drug therapy, enzymology, pathology, secondary)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, pathology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Female
• Humans
• Imidazoles (pharmacology)
• Immunohistochemistry
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Lung Neoplasms (drug therapy, enzymology, pathology)
• Mammary Neoplasms, Experimental (drug therapy, enzymology, pathology)
• Mice
• Mice, Nude
• Osteoclasts (drug effects, pathology)
• Piperidines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Macrophage Colony-Stimulating Factor (antagonists & inhibitors, blood, metabolism)
• Substrate Specificity
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, metabolism)