SandboxPKA: Difference between revisions
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[[Image:PONATINIB.jpg|thumb|left|Ponatinib bound to Abl]] | [[Image:PONATINIB.jpg|thumb|left|Ponatinib bound to Abl]] | ||
Ponatinib was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. | Ponatinib was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. It can inhibit, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations, like T315I mutation. The key structural feature of the molecule is a carbon-carbon triple bond linkage that makes productive hydrophobic contact with the side chain of I315, allowing inhibition of the T315I mutant. The triple bond also acts as an inflexible connector that enforces correct positioning of the two binding segments of AP24534 into their established binding pockets. AP24534 maintains an extensive hydrogen-bonding network and occupies a region of the kinase that overlaps significantly with the imatinib binding site. <ref>PMID:19878872</ref> | ||
<scene name='SandboxPKA/Ponatinib_bound_to_abl/1'>Ponatinib bound to c-Abl kinase domain</scene> | |||
== '''Resistance''' == | == '''Resistance''' == | ||