SandboxPKA: Difference between revisions
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On September 4, 2012, the U. S. Food and Drug Administration approved bosutinib tablets (Bosulif, Pfizer, Inc.) for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy. <ref>http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm</ref> | On September 4, 2012, the U. S. Food and Drug Administration approved bosutinib tablets (Bosulif, Pfizer, Inc.) for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy. <ref>http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm</ref> | ||
<scene name='SandboxPKA/Bosutinib/2'>Bosutinib's structure</scene> is based on a quinoline scaffold and is structurally related to the AstraZeneca quinazoline template. <ref> | <scene name='SandboxPKA/Bosutinib/2'>Bosutinib's structure</scene> is based on a quinoline scaffold and is structurally related to the AstraZeneca quinazoline template. <ref>PMID: 16172030</ref> | ||
==== Ponatinib (AP24534)==== | ==== Ponatinib (AP24534)==== | ||
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=== '''Resistance to second generation of TKI (Nilotinib/Dasatinib)'''=== | === '''Resistance to second generation of TKI (Nilotinib/Dasatinib)'''=== | ||
Nilotinib and Desatinib are ineffectiveness against the T315I mutant. It is important to underline that all mutations except T315I were effectively suppressed by increasing Nilotinib concentration. Although Dasatinib is much more potent than Imatinib it is possible, like with Nilotinib, that its specific mode of binding to Abl may lead to new vulnerable sites that could confer new kinds of drug resistance. Mutations have been found on Phe317 so that is a potential vulnerable site for this drug <ref> | Nilotinib and Desatinib are ineffectiveness against the T315I mutant. It is important to underline that all mutations except T315I were effectively suppressed by increasing Nilotinib concentration. Although Dasatinib is much more potent than Imatinib it is possible, like with Nilotinib, that its specific mode of binding to Abl may lead to new vulnerable sites that could confer new kinds of drug resistance. Mutations have been found on Phe317 so that is a potential vulnerable site for this drug <ref>PMID: 17591830</ref> | ||
=== '''Resistance to drugleads''' === | === '''Resistance to drugleads''' === | ||
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• '''Stopping Imatinib after cytgenetic remission''': in patients who achieve a complete molecular response (CMR), Bcr-Abl transcripts are no longer detectable by PCR. | • '''Stopping Imatinib after cytgenetic remission''': in patients who achieve a complete molecular response (CMR), Bcr-Abl transcripts are no longer detectable by PCR. | ||
• '''Allogeneic HCT (AlloHCT)''': use for those who are intolerant to TKIs or have mutations such as the T315I mutation, which can produce significant resistance to all of the clinically available TKIs. In addition, it seems that in high-risk or advanced-phase patients, a more aggressive approach would be to combine second-generation TKIs initially, followed by AlloHCT. <ref> | • '''Allogeneic HCT (AlloHCT)''': use for those who are intolerant to TKIs or have mutations such as the T315I mutation, which can produce significant resistance to all of the clinically available TKIs. In addition, it seems that in high-risk or advanced-phase patients, a more aggressive approach would be to combine second-generation TKIs initially, followed by AlloHCT. <ref>PMID: 18754032</ref> . | ||
• '''Autologous stem cell transplantation (auto-SCT)''': could also eliminate a Ph+ clone bearing a BCR-ABL kinase domain mutation, thus could be a promising therapeutic option for imatinib resistance. | • '''Autologous stem cell transplantation (auto-SCT)''': could also eliminate a Ph+ clone bearing a BCR-ABL kinase domain mutation, thus could be a promising therapeutic option for imatinib resistance. | ||
• '''ATP non-competitive ABL TKI''': useful for patients with the T315I mutation. Some examples are ON012380, the aurora kinase inhibitor MK-0457, and the p38 MAP kinase inhibitor BIRB796 <ref> | • '''ATP non-competitive ABL TKI''': useful for patients with the T315I mutation. Some examples are ON012380, the aurora kinase inhibitor MK-0457, and the p38 MAP kinase inhibitor BIRB796 <ref>PMID: 20537386</ref> . | ||
=='''Current situation'''== | =='''Current situation'''== | ||
