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 Journal Article
| Authors: | Huron, D. R.; Gorre, M. E.; Kraker, A. J.; Sawyers, C. L.; Rosen, N.; Moasser, M. M. |
| Article Title: | 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 |
| Abstract: | Inhibition of the constitutively active Bcr-abl tyrosine kinase (TK) by STI571 has proven to be a highly effective treatment for chronic myelogenous leukemia (CML). However, STI571 is only transiently effective in blast crisis, and drug resistance emerges by amplification of or development of mutational changes in Bcr-abl. We have screened a family of TK inhibitors of the pyrido [2,3-d]pyrimidine class, unrelated to STI571, and describe here a compound with substantial activity against STI-resistant mutant Bcr-abl proteins. This compound, PD166326, is a dual specificity TK inhibitor and inhibits src and abl in vitro with IC50s of 6 and 8 nM respectively. PD166326 inhibits the growth of K562 cells with IC50 of 300 pM, leading to apoptotic G1 arrest, whereas non-Bcr-abl cell types require >1000 times higher concentrations. We tested the effects of PD166326 on two of the clinically observed STI571-resistant Bcr-abl mutants. PD166326 potently inhibits the E255K mutant Bcr-abl protein and the growth of Bcr-ablE255K-driven cells. The T315I mutant Bcr-abl protein, which is mutated within the ATP-binding pocket, is resistant to PD166326; however, the growth of Bcr-ablT315I-driven cells is partially sensitive to this compound, likely through the inhibition of Bcr-abl effector pathways. These findings show that TK drug resistance is a structure-specific phenomenon and can be overcome by TK inhibitors of other structural classes, suggesting new approaches for future anticancer drug development. PD166326 is a prototype of a new generation of anti-Bcr-abl compounds with picomolar potency and substantial activity against STI571-resistant mutants. |
| Keywords: | unclassified drug; gene mutation; human cell; mutation; cancer growth; drug efficacy; antineoplastic agents; pyridines; cell cycle; imatinib; apoptosis; gene amplification; cancer cell culture; drug potency; dose-response relationship, drug; drug resistance, neoplasm; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; protein tyrosine kinase; chronic myeloid leukemia; drug specificity; pyrimidines; cancer resistance; protein tyrosine kinase inhibitor; blotting, western; enzyme inhibitors; bcr abl protein; piperazines; adenosine triphosphate; ic 50; inhibitory concentration 50; cell cycle g1 phase; g1 phase; fusion proteins, bcr-abl; blast cell crisis; 6 (2,6 dichlorophenyl) 8 methyl 2 (3 methylthioanilino) 8h pyrido[2,3 d]pyrimidin 7 one; k562 cells; proto-oncogene proteins c-abl; humans; human; priority journal; article; pd 166406; pd 179483 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 9 |
| Issue: | 4 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2003-04-01 |
| Start Page: | 1267 |
| End Page: | 1273 |
| Language: | English |
| PUBMED: | 12684394 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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