ABSTRACT
Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases. In 3 representative human cancer cell lines with different mechanisms of FGFR activation tested, SOMCL-085 (20-500 nmol/L) dose-dependently inhibited FGFR1-3 phosphorylation and the phosphorylation of their key downstream effectors PLCγ and Erk. In 7 FGFR aberrant human cancer cell lines, regardless of the mechanistic complexity of FGFR over-activation, SOMCL-085 potently inhibited FGFR-driven cell proliferation by arresting cells at the G1/S phase. In the FGFR1-amplified lung cancer cell line H1581 xenograft mice and FGFR2-amplified gastric cancer cell line SNU16 xenograft mice, oral administration of SOMCL-085 (25, 50 mg·kg-1·d-1) for 21 days substantially suppressed tumor growth without affecting their body-weight. These results suggest that SOMCL-085 is a potent multi-target FGFR inhibitor that inhibits the FGFR-dependent neoplastic phenotypes of human cancer cells in vitro and in vivo.
Subject(s)
Antineoplastic Agents/therapeutic use , Naphthalenes/therapeutic use , Piperazines/therapeutic use , Pyridines/therapeutic use , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Female , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Mice, Nude , Naphthalenes/administration & dosage , Naphthalenes/pharmacology , Piperazines/administration & dosage , Piperazines/pharmacology , Pyridines/administration & dosage , Pyridines/pharmacology , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
To compare oxidative dissolution rates of chalcopyrite by different consortia of moderately thermophilic acidophiles, various defined mixed cultures of three bacteria Acidithiobacillus caldus s2, Leptospirillum ferriphilum YSK, and Sulfobacillus sp. LN and one archaeon Ferroplasma thermophilum L1 were studied in batch shake flask cultures incubated at 45 degrees C. Chalcopyrite dissolution was determined by measuring variations of soluble copper, ferric iron, and pH. Microbial population dynamics involved in bioleaching process were monitored using real-time quantitative polymerase chain reaction (PCR) technology. The complex consortia containing both chemoautotrophic (L. ferriphilum and At. caldus) and chemomixotrophic (Sulfobacillus LN and F. thermophilum) moderate thermophiles were found to be the most efficient in all of those tested. Mutualistic interactions between physiologically distinct moderately thermophilic acidophiles, involving transformations of iron and sulfur and transfer of organic compound, were considered to play a critical role in promoting chalcopyrite dissolution. The real-time PCR assay was reliable to analyze population dynamics of moderate thermophiles in bioleaching systems, and the analysis results were consistent with physiological characteristics of these strains.
