SandboxPKA: Difference between revisions
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3. '''T315I mutation''': In the presence of Imatinib, cells that generate mutations in BCR-ABL can overcome the ability of this drug to inhibit cell division. Mutations that alter the Imatinib binding site without affecting the adenosine triphosphate binding site or the active site of the kinase are very effective at inducing drug resistance. The gatekeeper in c-Abl kinase is a smaller threonine (Thr 315) that is not an effective stabilizer of the R-spine, but mutation in this residue is the most common mechanism implicated in secondary drug resistance. Usually, the gatekeeper is substituted by isoleucine or methionine and avoids Gleevec entrance to ATP-binding domain [5]. | 3. '''T315I mutation''': In the presence of Imatinib, cells that generate mutations in BCR-ABL can overcome the ability of this drug to inhibit cell division. Mutations that alter the Imatinib binding site without affecting the adenosine triphosphate binding site or the active site of the kinase are very effective at inducing drug resistance. The gatekeeper in c-Abl kinase is a smaller threonine (Thr 315) that is not an effective stabilizer of the R-spine, but mutation in this residue is the most common mechanism implicated in secondary drug resistance. Usually, the gatekeeper is substituted by isoleucine or methionine and avoids Gleevec entrance to ATP-binding domain [5]. | ||
4. '''P-loop mutation''': the structure of Bcr-Abl contains two flexible loops, the ATP-binding P-loop and the activation loop. Mutations in these loops destabilize arrangement of the loops such that the kinase domain cannot assume the inactive conformation required for Imatinib binding. There are clinical data indicating that Bcr-Abl mutations in the P-loop is 70-100 fold less sensitive to imatinib compared with native Bcr-Abl. <ref> | 4. '''P-loop mutation''': the structure of Bcr-Abl contains two flexible loops, the ATP-binding P-loop and the activation loop. Mutations in these loops destabilize arrangement of the loops such that the kinase domain cannot assume the inactive conformation required for Imatinib binding. There are clinical data indicating that Bcr-Abl mutations in the P-loop is 70-100 fold less sensitive to imatinib compared with native Bcr-Abl. <ref>PMID:20537386</ref> | ||
5. '''Activation of different kinases''': although the 9:22 translocation is necessary to initiate CML, BCR-ABL is only one of several kinases capable of maintaining the proliferation rate of the cell while inhibiting apoptosis. | 5. '''Activation of different kinases''': although the 9:22 translocation is necessary to initiate CML, BCR-ABL is only one of several kinases capable of maintaining the proliferation rate of the cell while inhibiting apoptosis. | ||
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=== '''Resistance to drugleads''' === | === '''Resistance to drugleads''' === | ||
T315 mutation is resistant to Bosutinib. In contrast to imatinib, nilotinib and dasatinib, bosutinib is not an efficient substrate for multidrug resistance (MDR) transporters that promotes efflux of foreign molecules from cells. Bosutinib even inhibits these transporter proteins in higher concentrations. <ref>Boschelli, F.; Arndt, K.; Gambacorti-Passerini, C. (2010). "Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia". European journal of cancer (Oxford, England : 1990) 46 (10): 1781–1789.doi:10.1016/j.ejca.2010.02.032. PMID 20399641. edit)</ref> | T315 mutation is resistant to Bosutinib. In contrast to imatinib, nilotinib and dasatinib, bosutinib is not an efficient substrate for multidrug resistance (MDR) transporters that promotes efflux of foreign molecules from cells. Bosutinib even inhibits these transporter proteins in higher concentrations. <ref>Boschelli, F.; Arndt, K.; Gambacorti-Passerini, C. (2010). "Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia". European journal of cancer (Oxford, England : 1990) 46 (10): 1781–1789.doi:10.1016/j.ejca.2010.02.032. PMID 20399641. edit)</ref> | ||
== '''New strategies in controlling drug resistance'''== | == '''New strategies in controlling drug resistance'''== | ||