Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance Journal Article
| Authors: | Azam, M.; Nardi, V.; Shakespeare, W. C.; Metcalf, C. A. 3rd; Bohacek, R. S.; Wang, Y.; Sundaramoorthi, R.; Sliz, P.; Veach, D. R.; Bornmann, W. G.; Clarkson, B.; Dalgarno, D. C.; Sawyer, T. K.; Daley, G. Q. |
| Article Title: | Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance |
| Abstract: | Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM R) BCR/ABL kinase variants. Both compounds potently inhibit most IM R variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM R-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance. © 2006 by The National Academy of Sciences of the USA. |
| Keywords: | controlled study; unclassified drug; gene mutation; mutation; nonhuman; pyridines; drug targeting; animal cell; mouse; imatinib; combination chemotherapy; cytotoxicity; drug potency; drug resistance; enzyme inhibitor; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; abelson kinase; protein tyrosine kinase; chronic myeloid leukemia; drug selectivity; pyrimidines; cancer resistance; protein kinase inhibitors; models, molecular; protein structure, tertiary; molecular structure; protein-tyrosine kinases; bcr abl protein; piperazines; conformational transition; adenosine triphosphate; src-family kinases; mutagenesis; drug binding; molecular model; chronic myelogenous leukemia; enzyme conformation; kinase inhibitors; proto-oncogene proteins c-abl; 2 cyclopentyl n [4 (dimethylphosphoryl)phenyl] 9 ethyl 9h purin 6 amine; 2 cyclopentyl n [4 (dipropylphosphoryl)phenyl] 9h purin 6 amine; 3 [2 [2 cyclopentyl 6 [4 (dimethylphosphoryl)phenylamino] 9h purin 9 yl]ethyl]phenol; 3 [2 [2 cyclopentyl 6 [4 (dipropylphosphoryl)phenylamino] 9h purin 9 yl]ethyl]phenol; 6 (2,6 dichlorophenyl) 2 (3 hydroxymethylphenylamino) 8 methyl 8h pyrido[2,3 d]pyrimidine 7 one; [4 [2 cyclopentyl 9 (3 hydroxyphenethyl)purin 6 ylamino]phenyl]dimethylphosphine oxide; ap 23846; ap 23848; ap 23980 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 103 |
| Issue: | 24 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2006-06-13 |
| Start Page: | 9244 |
| End Page: | 9249 |
| Language: | English |
| DOI: | 10.1073/pnas.0600001103 |
| PUBMED: | 16754879 |
| PROVIDER: | scopus |
| PMCID: | PMC1482597 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 69" - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus" |
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