Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors Journal Article
| Authors: | Von Bubnoff, N.; Veach, D. R.; Miller, W. T.; Li, W.; Sänger, J.; Peschel, C.; Bornmann, W. G.; Clarkson, B.; Duyster, J. |
| Article Title: | Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors |
| Abstract: | Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib. Mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. We aimed to examine whether pyrido-pyrimidine-type kinase inhibitors were capable of inhibiting both wild-type and mutant forms of BCR-ABL. We screened 13 different pyrido-pyrimidine with cells expressing wild-type and mutant BCR-ABL. All of the substances specifically suppressed the Bcr-Abl dependent phenotype and inhibited Bcr-Abl kinase activity with higher potency than imatinib. Two of the most active compounds were PD166326 and SKI DV-M016. Interestingly, these compounds suppressed the activation loop mutant Bcr-Abl H396P as effectively as wild-type Bcr-Abl. In addition, nucleotide-binding loop mutations (Y253H, E255K, and E255V) were selectively and potently inhibited. In contrast, T3151, a mutant located at a position that makes a direct contact with imatinib, was not affected. This observation is consistent with the hypothesis that unlike imatinib, pyrido-pyrimidine inhibitors bind Bcr-Abl regardless of the conformation of the activation loop. We conclude that pyrido-pyrimidine-type kinase inhibitors are active against different frequently observed kinase domain mutations of BCR-ABL that cause resistance toward imatinib. Resistance as a consequence of selection of mutant BCR-ABL by imatinib may be overcome using second-generation kinase inhibitors because of their higher potency and their ability to bind Bcr-Abl irrespective of the conformation of the activation loop. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; pyridines; cell proliferation; animal cell; mouse; phenotype; animals; mice; cell division; imatinib; apoptosis; enzyme activity; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; chronic myeloid leukemia; pyrimidines; protein kinase inhibitors; cancer inhibition; enzyme inhibitors; cell line, transformed; bcr abl protein; piperazines; adenosine triphosphate; point mutation; pyrimidine derivative; phosphotransferase inhibitor; fusion proteins, bcr-abl; philadelphia 1 chromosome; enzyme conformation; 6 (2,6 dichlorophenyl) 2 (4 fluoro 3 methylanilino) 8 methyl 8h pyrido[2,3 d]pyrimidin 7 one; 6 (2,6 dichlorophenyl) 8 methyl 2 (3 methylthioanilino) 8h pyrido[2,3 d]pyrimidin 7 one; pd 173956; pd 173958; leukemia, myeloid, philadelphia-positive; humans; human; priority journal; article; leukemia, lymphocytic, acute, l2; 6 (2,6 dichlorophenyl) 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; pyrido[2,2 d]pyrimidine derivative; ski dv 1 10; ski dv 2 43; ski dv 2 47; ski dv 2 87; ski dv 2 89; ski dv m016; ski dv m017; ski dv s 43 |
| Journal Title: | Cancer Research |
| Volume: | 63 |
| Issue: | 19 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2003-10-01 |
| Start Page: | 6395 |
| End Page: | 6404 |
| Language: | English |
| PUBMED: | 14559829 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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