There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colonystimulating 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.
R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.
The ␣ V integrins are key receptors involved in mediating cell migration and angiogenesis. In age-related macular degeneration (AMD) and diabetic retinopathy, angiogenesis plays a critical role in the loss of vision. These ocular vasculopathies might be treatable with a suitable ␣ V antagonist, and an oral drug would offer a distinct advantage over current therapies. (3,S,,S)-1,2,3,4-Tetrahydro-- [[1-[1-oxo-3-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-quinolinepropanoic acid (JNJ-26076713) is a potent, orally bioavailable, nonpeptide ␣ V antagonist derived from the arginine-glycine-asparagine binding motif in the matrix protein ligands (e.g., vitronectin). This compound inhibits ␣ V  3 and ␣ V  5 binding to vitronectin in the low nanomolar range, it has excellent selectivity over integrins ␣ IIb  3 and ␣ 5  1 , and it prevents adhesion to human, rat, and mouse endothelial cells. JNJ-26076713 blocks cell migration induced by vascular endothelial growth factor, fibroblast growth factor (FGF), and serum, and angiogenesis induced by FGF in the chick chorioallantoic membrane model. JNJ-26076713 is the first ␣ V antagonist reported to inhibit retinal neovascularization in an oxygen-induced model of retinopathy of prematurity after oral administration. In diabetic rats, orally administered JNJ-26076713 markedly inhibits retinal vascular permeability, a key early event in diabetic macular edema and AMD. Given this profile, JNJ-26076713 represents a potential therapeutic candidate for the treatment of age-related macular degeneration, macular edema, and proliferative diabetic retinopathy.Age-related macular degeneration (AMD) is the leading cause of blindness in people over 55 years of age, and diabetic retinopathy (DR) in people under 55 years of age (Klein et al., 1994;Williams et al., 2004). Both disease conditions are characterized by new blood vessel growth-choroidal neovascularization in AMD and retinal neovascularization in DR (Freund, 1993;Speicher et al., 2003;Williams et al., 2004;Zarbin, 2004). There is ample evidence that ␣ V integrins are involved in ocular angiogenesis. Proangiogenic growth factors, including VEGF and FGF, are up-regulated in AMD and DR and they stimulate ␣ V expression. In the well established mouse model of oxygen-induced retinopathy (OIR), or retinopathy of prematurity (ROP) model, ␣ V integrins and the Article, publication date, and citation information can be found at
A series of monosaccharides containing a biguanide functionality was prepared and evaluated for hypoglycemic activity. Among the analogues prepared were those involving D-glucose substituted on the 6- or 1-position (19 and 24), D-galactose substituted on the 6-position (7), and D-arabinose (31). The target compounds were evaluated in a modified rat glucose-tolerance test (oral glucose load/oral drug, 100 mg/kg). Compounds 8 [6-biguanidino-1,2:3,5-bis-O-(1-methylethylidene)-6-deoxy-al pha-D- glucofuranose] and 23 [methyl 6-biguanidino-6-deoxy-2,3,4-O-tribenzyl-alpha-D-glucopyra nos ide] were the most active, exhibiting nearly equivalent hypoglycemic activity to that of phenformin (1) and metformin (2), as measured by the inhibition of the rise of blood glucose. Compound 31 was somewhat less active with 26% inhibition, as compared to 64% inhibition with 1 and 41% inhibition with 2.
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