Strategic therapeutic approaches to overcome emerging dual SRC/ABL kinase inhibitors resistances in chronic phase Ph positive chronic myeloid leukemia
Chronic myeloid leukemia (CML) is a haematopoietic neoplasm with clinically distinct phases and BCR⁄ABL1 oncogene. Imatinib mesylate, a potent inhibitor of BCR-ABL was highly effective in CML but later in-vitro derived cell line with resistance namely BCR-ABL duplication point mutation, P loop mutat...
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| Format: | Article |
| Language: | English |
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Manipal College of Medical Sciences, Pokhara
2014-07-01
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| Series: | Asian Journal of Medical Sciences |
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| Online Access: | https://www.nepjol.info/index.php/AJMS/article/view/10454 |
| Summary: | Chronic myeloid leukemia (CML) is a haematopoietic neoplasm with clinically distinct phases and BCR⁄ABL1 oncogene. Imatinib mesylate, a potent inhibitor of BCR-ABL was highly effective in CML but later in-vitro derived cell line with resistance namely BCR-ABL duplication point mutation, P loop mutation, T315I mutation, C helix, SH2 domain, activation loop, C terminal lobe, SRC family kinase activation led to development of Nilotinib. Although it has potential drug targets as BCR-ABL kinase, KIT, PDGFR but has no role in overcoming in Src family kinase. It prompted strategic rational drug design of Dual Src Family Kinase/Abl Inhibitor Dasatinib, active against 15 clinically significant Imatinib resistant BCR-ABL mutations but inactive against T315I mutation. The propensity of Ph+ CML to develop novel mechanism of resistance led designing of rational therapeutic approaches to eradicate minutest residual diseases along with long term resistance risk. |
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| ISSN: | 2467-9100 2091-0576 |