title: 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.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477, USA. cmanthey@its.jnj.com
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Dana L
authors.initials: DL
authors.lastname: Johnson
authors.forename: Carl R
authors.initials: CR
authors.lastname: Illig
authors.forename: Robert W
authors.initials: RW
authors.lastname: Tuman
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Judith F
authors.initials: JF
authors.lastname: Baker
authors.forename: Margery A
authors.initials: MA
authors.lastname: Chaikin
authors.forename: Robert R
authors.initials: RR
authors.lastname: Donatelli
authors.forename: Carol F
authors.initials: CF
authors.lastname: Franks
authors.forename: Lee
authors.initials: L
authors.lastname: Zeng
authors.forename: Carl
authors.initials: C
authors.lastname: Crysler
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Chen
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Yurkow
authors.forename: Lisa
authors.initials: L
authors.lastname: Boczon
authors.forename: Sanath K
authors.initials: SK
authors.lastname: Meegalla
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wilson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wall
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Chen
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Heidi
authors.initials: H
authors.lastname: Ott
authors.forename: Christian
authors.initials: C
authors.lastname: Baumann
authors.forename: Danielle
authors.initials: D
authors.lastname: Lawrence
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Molloy
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C549569:4-cyano-N-(2-(1-cyclohexen-1-yl)-4-(1-((dimethylamino)acetyl)-4-piperidinyl)phenyl)-1H-imidazole-2-carboxamide; D007093:Imidazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051941:fms-Like Tyrosine Kinase 3