The properties of several multitargeted receptor tyrosine kinase inhibitors have been studied for their inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling. A structurally novel, multitargeted tyrosine kinase inhibitor (ABT-869), imatinib (STI571), and four compounds currently in clinical development (AG013736, BAY 43-9006, CHIR258, and SU11248) were tested for inhibition of CSF-1R signaling in both the enzymatic and cellular assays. ABT-869 showed potent CSF-1R inhibition in both the enzyme and cell-based assays (IC50s < 20 nmol/L). In contrast to a previous report, we have found that imatinib has activity against human CSF-1R in both assays at submicromolar concentrations. In enzyme assays, we have found that the inhibition of CSF-1R by both ABT-869 and imatinib are competitive with ATP, with Ki values of 3 and 120 nmol/L, respectively. SU11248 is a potent inhibitor of CSF-1R in the enzyme assay (IC50 = 7 nmol/L) and inhibits receptor phosphorylation in the cellular assay (IC50 = 61 nmol/L). AG013736 was also a potent inhibitor of CSF-1R in both assays (enzyme, IC50 = 16 nmol/L; cellular, IC50 = 21 nmol/L), whereas BAY 43-9006 is less potent in the enzyme assay (IC50 = 107 nmol/L) than in the cellular system (IC50 = 20 nmol/L). In contrast, we found that CHIR258 had less activity in the cellular assay (IC50 = 535 nmol/L) relative to its enzymatic potency (IC50 = 26 nmol/L). These results show the use of a cell-based assay to confirm the inhibitory activity of lead compounds and drug candidates, such as ABT-869, against the CSF-1R protein in situ.
"Linifanib (ABT-869) is an orally active novel small molecule multi-target receptor tyrosine kinase (RTK) inhibitor, which simultaneously inhibits VEGFR and PDGFR with minimal activity against unrelated RTKs. It has potent inhibitory activity against VEGFR-1, VEGFR-2, PDGFRb, colony-stimulating factor 1 receptor, and fms-related tyrosine kinase 3, with minimal activity against unrelated tyrosine and serine/threonine kinases [3-5]. Linifanib has shown prominent antitumor activity against solid tumors in phase 2 studies e.g. "
[Show abstract][Hide abstract] ABSTRACT: Linifanib (ABT-869) is an orally active receptor tyrosine kinase inhibitor, which simultaneously inhibits vascular endothelial and platelet derived growth factor receptor. The aim of the present study was to develop an UHPLC-MS/MS method for the quantification of linifanib in rat plasma to support the pharmacokinetic and toxicokinetic studies.
Linifanib was separated on Acquity UPLC BEHTM C18 column (50 x 2.1 mm, i.d. 1.7 mum) using acetonitrile-10 mM ammonium acetate (60:40, v/v) as an isocratic mobile phase at a flow rate of 0.3 mL/min with sunitinib as internal standard (IS). Detection was performed on tandem mass spectrometer using electrospray ionization source in positive mode by multiple reaction monitoring. The monitored transitions were set at m/z 376.05 > 250.97 for linifanib and m/z 399.12 >283.02 for IS, respectively. Both linifanib and IS were eluted at 0.68 and 0.44 min, respectively with a total run time of 2.0 min only. The calibration curve was found to be linear over the concentration range of 0.40-500 ng/mL. The intra- and inter-day precision value was <=10.6%and the accuracy ranged from 90.9-108.9%. In addition, all the validation results were within general assay acceptability criteria according to guidelines of bio-analytical method validation.
A selective and sensitive UHPLC-MS/MS method was developed and validated for the determination of linifanib in rat plasma for the first time. The developed method is simple, sensitive and rapid in terms of chromatographic separation and sample preparation and was successfully applied in a pilot pharmacokinetic study in rats.
Chemistry Central Journal 02/2014; 8(1):13. DOI:10.1186/1752-153X-8-13 · 2.19 Impact Factor
"Linifanib (ABT-869) is a novel, potent inhibitor with selectivity for the VEGFR and PDGFR family of receptor tyrosine kinases. It has specific inhibitory activity against VEGFR-1, VEGFR-2, PDGFRβ, colony-stimulating factor 1 receptor, and fms-related tyrosine kinase 3, with minimal activity against unrelated tyrosine and serine/threonine kinases [9–11]. In preclinical studies with multiple human tumor xenograft models, linifanib demonstrated potent antiangiogenic and antitumor effects [9–13]. "
[Show abstract][Hide abstract] ABSTRACT: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors.
Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors.
Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks).
Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.
Cancer Chemotherapy and Pharmacology 03/2012; 69(6):1477-86. DOI:10.1007/s00280-012-1846-6 · 2.77 Impact Factor
"The expression of c-fms in normal tissue, on the other hand, is limited to macrophages, except during pregnancy , making it a better target for therapy, although indiscriminate destruction of macrophages can have serious consequences for health, including decreased liver function and vulnerability to infectious diseases. Nevertheless, a number of agents have been developed to specifically target c-fms, as well as some multitargeted agents, showing c-fms inhibition in enzyme and cell-based assays . Currently, three phase 1 clinical trials involving c-fms inhibitors are recruiting patients (NCT01004861, NCT01316822, and NCT01346358) (clinicaltrials.gov, "
[Show abstract][Hide abstract] ABSTRACT: Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs), which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative) phenotype. The interaction between tumor cells and macrophages provides opportunities for therapy. This paper will discuss secreted proteins as targets for intervention.
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