Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays

Journal of Medicinal Chemistry

Volumn 47, Issue 27, 2004, Pages 6658-6661

  Lombardo, Louis J ^a   Lee, Francis Y ^a   Chen, Ping ^a   Norris, Derek ^a   Barrish, Joel C ^a   Behnia, Kamelia ^a   Castaneda, Stephen ^a   Cornelius, Lyndon A M ^a   Das, Jagabandhu ^a   Doweyko, Arthur M ^a   Fairchild, Craig ^a   Hunt, John T ^a   Inigo, Ivan ^a   Johnston, Kathy ^a   Kamath, Amrita ^a   Kan, David ^a   Klei, Herbert ^a   Marathe, Punit ^a   Pang, Suhong ^a   Peterson, Russell ^a   Pitt, Sidney ^a   Schieven, Gary L ^a   Schmidt, Robert J ^a   Tokarski, John ^a   Wen, Mei Li ^a   Wityak, John ^a   Borzilleri, Robert M ^a   more..

^a BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (AMINOPYRIDYL)THIAZOLE 5 CARBOXAMIDE; 2 (AMINOPYRIMIDINYL)THIAZOLE 5 CARBOXAMIDE; ABELSON KINASE; ABL KINASE INHIBITOR; ANTINEOPLASTIC AGENT; DASATINIB; PROTEIN TYROSINE KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; ARTICLE; CHRONIC MYELOID LEUKEMIA; DOSE RESPONSE; DRUG ACTIVITY; NONHUMAN; RAT; TUMOR REGRESSION; XENOGRAFT;

ADENOSINE TRIPHOSPHATE; ANIMALS; ANTINEOPLASTIC AGENTS; ENZYME INHIBITORS; HUMANS; K562 CELLS; MICE; PROTO-ONCOGENE PROTEINS C-ABL; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; SRC-FAMILY KINASES; THIAZOLES;

EID: 19944428353     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049486a     Document Type: Article

References (13)

1. O'Dwyer, M. E.; Mauro, M. J.; Druker, B. J. STI571 as a targeted therapy for CML. Cancer Invest. 2003, 21, 429-438.
2. Frame, M. C. Src in cancer: deregulation and consequences for cell behaviour. Biochim. Biopfiys. Acta 2002, 1602, 114-130.
3. lck. Bioorg. Med. Chem. Lett. 2003, 13, 4007-4010.
4. lck inhibitor. Bioorg. Med. Chem. Lett, in press.
5. Antiproliferative activities were determined based on tetrazolium dye conversion following 72 h drug exposure. Details of the assay and culture conditions for the tumor cell lines are contained in the following reference: Lee, F. Y. F.; Borzilleri, R. M.; Fairchild, C. R.; Kim, S. H.; Long, B. H.; Reventos-Suarez, C.; Vite, G. D.; Rose, W. C.; Kramer, R. A. BMS-247550: A novel epothilone analogue with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin. Cancer Res. 2001, 7, 1429-1437.
6. Begtrup, M.; Hansen, L. B. New methods for the introduction of substituents into thiazoles. Acta Chem. Scand. 1992,46, 372-383.
7. Saito, J.; Tamura, T.; Morishima, N. JP 50,089,344, 1975.
8. Ueno, K; Kinoene, M.; Minami, T. JP 43,005,394, 1968.
9. Commercially available from Sigma-Aldrich Corporation.
10. Nagar, B.; Bornmann, W. G.; Pellicena, P.; Schindler, T.; Veach, D. R.; Miller, W. T.; Clarkson, B.; Kuriyan, J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002, 62, 4236.
11. Huron, D. R.; Gorre, M. E.; Kraker, A. J.; Sawyers, C. L.; Rosen, N.; Moasser, M. M. A novel pyridopyrimidine inhibitor of Abl kinase is a picomolar inhibitor of Bcr-Abl-driven K562 cells and is effective against STI571-resistant Bcr-Abl mutants. Clin. Cancer. Res. 2003, 9, 1267-1273.
12. Shah, N. P.; Tran, C.; Lee, F. Y.; Chen, P.; Norris, D.; Sawyers, C. L. Overriding imatinib resistance with a novel Abl kinase inhibitor. Science 2004, 305, 399-401.
13. Xu, W.; Doshi, A.; Lei, M.; Eck, M, J.; Harrison, S, C, Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol. Cell 1999, 3, 629-638.