Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 7, 2006, Pages 1950-1953

  McDermott, Lee A ^a   Higgins, Brian ^a   Simcox, Mary ^a   Luk, Kin Chun ^a   Nevins, Tom ^a   Kolinsky, Kenneth ^a   Smith, Melissa ^a   Yang, Hong ^a   Li, Jia K ^a   Chen, Yingsi ^a   Ke, June ^a   Mallalieu, Navita ^a   Egan, Tom ^a   Kolis, Stan ^a   Railkar, Aruna ^a   Gerber, Louise ^a   Liu, Jin Jun ^a   Konzelmann, Fred ^a   Zhang, Zhuming ^a   Flynn, Tom ^a   Morales, Omar ^a   Chen, Yi ^a   more..

^a HOFFMANN LA ROCHE INC   (United States)

Author keywords

Biological results; FGFR; Inhibitor; KDR; PDGFR; Pyrimidopyrimidone

Indexed keywords

FIBROBLAST GROWTH FACTOR RECEPTOR; GROWTH FACTOR RECEPTOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PYRIMIDINE DERIVATIVE; RECEPTOR BLOCKING AGENT; RO 4396686; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 2;

ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER INHIBITION; CELL PROLIFERATION; CONTROLLED STUDY; CORNEA NEOVASCULARIZATION; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG SCREENING; HUMAN; HUMAN CELL; IC 50; LOW DRUG DOSE; LUNG NON SMALL CELL CANCER; MOUSE; NONHUMAN; RECEPTOR BLOCKING; TUMOR VOLUME; XENOGRAFT;

ANGIOGENESIS INHIBITORS; ANIMALS; MICE; MICE, NUDE; NEOPLASMS, EXPERIMENTAL; NEOVASCULARIZATION, PATHOLOGIC; PYRIMIDINES; RATS; RATS, WISTAR; RECEPTORS, FIBROBLAST GROWTH FACTOR; RECEPTORS, PLATELET-DERIVED GROWTH FACTOR; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

ANIMALIA; RODENTIA;

EID: 33144460233     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.092     Document Type: Article

References (22)

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19. Human umbilical vein endothelial cells (HUVEC, Clonetics cat. CC-2519) were cultured according to manufacturer's protocol. Cell passages 2-6 were used to determine VEGF- or bFGF-stimulated proliferation. Subconfluent cultures were serum starved for 24 h, followed by addition of test compound. After 2 h incubation with drug, 20 ng/mL VEGF (R&D Systems, cat.#293-VE) or 5 ng/mL bFGF (purified, recombinant) was added. DNA synthesis was evaluated using BrdU incorporation (Roche Biochemicals, cat. #1-647-229). After 20 h of incubation with compound, BrdU labeling reagent was added. Four hours later, incorporated label was quantitated using a peroxidase-conjugated BrdU antibody and colorimetric detection.
20. Exponentially growing tumor cells were plated in 96-well microtiter plates and incubated overnight at 37°C prior to compound addition. Proliferation was assessed by measurement of formazan formation from MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) (Sigma) during a 2.5 h incubation 6 days after initial plating.
21. Single doses of the test compound were administered intravenously and orally to athymic nude mice and Wistar rats. In mice, the test agent was administered at a dose level of 10 mg/kg iv, and at doses of 50 and 200 mg/kg po. Blood samples were collected from the retro-orbital sinus or via terminal cardiac puncture at 1, 5, 15, 30 min, and 1, 2, 4, 8, 16, and 24 h postdose after iv dosing and 5, 15, 30 min, and 1, 2, 4, 8, 16, and 24 h postdose after oral dosing. In Wistar rat, a 5 mg/kg single dose of test compound was administered iv via a femoral arterial catheter. Again two oral doses of 50 and 200 mg/kg were used to determine oral absorption characteristics. Blood samples were collected via an implanted jugular catheter at 1, 7, 15, 30 min, and 1, 3, 6, 12, and 24 h postdose after iv dosing and at 5, 15, 30 min, and 1, 3, 6, 12, 24, and 48 h postdose after oral dosing. In all iv experiments, the test compound was formulated in 2% DMA, 10% PEG400, and 88% of 40% HPBCD in water. The oral formulation was 2% Klucel LF and 0.1% Tween 80 in water. Blood samples were collected in EDTA-containing tubes and centrifuged. The plasma was then removed and stored at -70°C until analysis. For the analysis of samples a specific LC-MS/MS assay was developed. Fifty microliters of samples was extracted by precipitation of plasma proteins with acetonitrile. The supernatant was diluted with water before injecting onto a C18 (Zorbax® SB-C18 5 μm 2.1 × 50 mm) LC column connected to an LC-MS/MS system. Standard and QC samples were injected together with study samples. All concentrations were interpolated from calibration curves (ranged from 1 to 2000 ng/mL) and all PK parameters were calculated using a Watson laboratory information system (LIMS) software program (version 6.3.0.01a).
22. For an overview of the CPA and other assays in use for the assessment of angiogenesis in vivo and in vitro, see: R. Auerbach, R. Lewis, B. Shinners, L. Kubai, and N. Akhtar Clin. Chem. 49 2003 32