SandboxPKA: Difference between revisions

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==== Bosutinib (SKI-606)====

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>

Bosutinib has been seen to be active in chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. <ref>PMID: 22371878</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+) 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>PMID: 16172030</ref>

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[[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. ~~The substance potently inhibits~~, 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>

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>

<scene name='52/521153/Ponatinib_bound_to_abl/2'>Ponatinib bound to c-Abl kinase domain</scene>

== '''Resistance''' ==

SandboxPKA: Difference between revisions

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@@ Line 132: / Line 132: @@
 ==== Bosutinib  (SKI-606)====
-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>
+Bosutinib has been seen to be active in chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. <ref>PMID: 22371878</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+) 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>PMID: 16172030</ref>
@@ Line 140: / Line 140: @@
 [[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. The substance potently inhibits, 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>
+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>
+<scene name='52/521153/Ponatinib_bound_to_abl/2'>Ponatinib bound to c-Abl kinase domain</scene>
 == '''Resistance''' ==