Pyrazolo[3,4-d]pyrimidines as potent inhibitors of the insulin-like growth factor receptor (IGF-IR)

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 19, 2007, Pages 5406-5409

  Hubbard, Robert D ^a   Bamaung, Nwe Y ^a   Palazzo, Fabio ^a   Zhang, Qian ^a   Kovar, Peter ^a   Osterling, Donald J ^a   Hu, Xiaoming ^a   Wilsbacher, Julie L ^a   Johnson, Eric F ^a   Bouska, Jennifer ^a   Wang, Jieyi ^a   Bell, Randy L ^a   Davidsen, Steven K ^a   Sheppard, George S ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

Inhibitor; Insulin like growth factor receptor (IGF IR); Kinase; Pyrazolo 3,4 d pyrimidine

Indexed keywords

BENZIMIDAZOLE DERIVATIVE; FORMIC ACID; MORPHOLINE; PHOSPHOTRANSFERASE INHIBITOR; PYRAZOLO[3,4 D]PYRIMIDINE DERIVATIVE; PYRAZOLOPYRIMIDINE DERIVATIVE; SOMATOMEDIN RECEPTOR;

ARTICLE; CANCER CHEMOTHERAPY; DRUG CLASSIFICATION; DRUG INHIBITION; DRUG POTENCY; INHIBITION KINETICS; SYNTHESIS;

ADMINISTRATION, ORAL; ANIMALS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; INJECTIONS, INTRAVENOUS; MICE; PHOSPHORYLATION; PYRAZOLES; PYRIMIDINES; RECEPTOR PROTEIN-TYROSINE KINASES; RECEPTORS, SOMATOMEDIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34548552538     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.07.037     Document Type: Article

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19. 2, 0.1% BSA, and 1 mM DTT, 40 μL final volume).
20. MiaPaCa-2 cells were treated with serial dilutions (0.0003-30 μM) of compounds for 6 h in growth media containing 10% fetal bovine serum before stimulation with IGF-I for 10 min. Cells were then lysed and phosphorylation of IGF-IR was determined using the human p-IGF-IR DuoSet IC ELISA kit from R&D Systems (Minneapolis, MN).
21. A pharmacodynamic model to determine the activity of IGF-IR kinase inhibitor in mice was adapted from Garci{dotless}́a-Echeverri{dotless}́a, C. Pearson, M. A.; Marti, A.; Meyer, T.; Mestan, J.; Zimmermann, J.; Gao, J.; Brueggen, J.; Capraro, H.-G.; Cozens, R.; Evans, D. B.; Hofman, D. Cancer Cell 2004, 5, 231. Compound 14 or vehicle was administered orally at 12.5 mg/kg in C57BL6 mice; 4 h later IGF-I at 0.5 mg/kg was injected intravenously, and the lung tissue was collected 10 min thereafter. p-IGF-IR and total IGF-IR in lung tissue lysates were determined by Western Blot using specific antibodies (Biosource, Camarillo, CA and Santa Cruz Biotechnology, Inc., Santa Cruz, CA).