SandboxPKA: Difference between revisions
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2. '''Drug efflux''': Imatinib is a substrate for the P-glycoprotein pump, which can result in decreased intracellular concentrations of Imatinib. | 2. '''Drug efflux''': Imatinib is a substrate for the P-glycoprotein pump, which can result in decreased intracellular concentrations of Imatinib. | ||
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 | 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. | ||
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> | 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> | ||