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Potatinib was developed as a treatment option for chronic myeloid leukemia (CML) as other inhibitors in treatment have become ineffective. BCR-ABL is a kinase with cancerous genetic mutation in chromosome 22 that leaves it always active. Further mutations in BCR-ABL has left earlier drugs of tyrosine kinases unable to bind in almost 30% of cases over a course of five years of treatment. The newer, mutant BCR-ABL kinase’s ability to develop new resistances has pushed for newer developments in inhibitors, such as Potatinib<ref name="seven">PMID: 21118377 </ref>.
Potatinib was developed as a treatment option for chronic myeloid leukemia (CML) as other inhibitors in treatment have become ineffective. BCR-ABL is a kinase with cancerous genetic mutation in chromosome 22 that leaves it always active. Further mutations in BCR-ABL has left earlier drugs of tyrosine kinases unable to bind in almost 30% of cases over a course of five years of treatment. The newer, mutant BCR-ABL kinase’s ability to develop new resistances has pushed for newer developments in inhibitors, such as Potatinib<ref name="seven">PMID: 21118377 </ref>.
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Fibroblast growth factor (FGFR) signaling is the factor that normally activates the BCR-ABL kinase. Also, it is the protein behind both tissue development and repair. The activation of BCR-ABL happens through a series of cascading signals that induce proliferation and migration in cells. Though mutations in the regulation of the FGFR tyrosine kinase family can result in malignant tumor growth<ref name="two" />. The tyrosine kinase inhibitor Ponatinib has been used to
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Fibroblast growth factor (FGFR) signaling is the factor that normally activates the BCR-ABL kinase. Also, it is the protein behind both tissue development and repair, the disruption of which leads to tumor growth. The activation of BCR-ABL happens through a series of cascading signals that induce proliferation and migration in cells. Though mutations in the regulation of the FGFR tyrosine kinase family can result in malignant tumor growth<ref name="two" />. The tyrosine kinase inhibitor Ponatinib has been used to <scene name='48/483882/Activation_loop/1'>bind</scene> to the mutant version of kinase BCR-ABL by the enzyme's specific "DFG-out" conformation. This conformation has the phenylalanine group of BCR-ABL flipped out of its hydrophobic binding site. Ponatinib is the first of its kind to be able to inhibit this specific mutation in BCR-ABL of the "DGF-out" combination<ref name="two" />.
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<scene name='48/483882/Activation_loop/1'>bind</scene> to the mutant version of kinase BCR-ABL by the kinase's specific "DFG-out" conformation. The "DFG-out" conformation has the phenylalanine group of BCR-ABL flipped out of its hydrophobic binding site. Ponatinib is the first of its kind to be able to inhibit this specific mutation in BCR-ABL of the "DGF-out" combination<ref name="two" />.
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The side effects of have caused Ponatinib to fall under scrutiny from the U.S. Food and Drug Administration (FDA). Ponatinib has shown to increase chances of deadly blood clotting and restenosis in both arteries and veins with a rate of about 1 in 5 patients. The drug has also shown to increase risk of heart attack and overall worsening of heart disease in patients<ref name="seven" />.
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The side effects have caused Ponatinib to fall under scrutiny from the U.S. Food and Drug Administration (FDA). It has shown to increase chances of deadly blood clotting and restenosis in both arteries and veins with a rate of about 1 in 5 patients. The drug has also shown to increase risk of heart attack and overall worsening of heart disease in patients<ref name="seven" />.
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----------'''Notes (to be removed)'''
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**Note: the green scene "bind" shows the secondary structure with two key residues in the activation loop (highlighted in light blue) for Ponatinab binding..can be changed, the activation loop is not the only thing involved in binding. A potential fit for this section though.
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Fibrolast Growth Factor Receptor (FGFR) plays a role in causing a variety of cancers. FGFR plays a role in the signaling system with FGF by initiating signaling cascades that control development and tissue repair. The disruption of this signaling system is involved in tumor growth<ref name="one" />
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Ponatinib is a relatively new anti-cancer drug that inhibits FGFR. While most inhibitors are selective for FGFR1-3 and show a reduced binding to FGFR4, Ponatinib binds to FGFR4<ref name="one" />. Further, the drug is a Bcr-Abl tyrosine kinase inhibitor (TKI)<ref name="one" />. Ponatinib is specifically prescribed to patients with chronic myeloid leukemia and Philadelphia-chromosome positive active lymphoblastic leukemia. Although, it has recently shown side effects causing blood clots and narrowing blood vessels.
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•Plays a role in a variety of cancers
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•Ponatinib is a drug prescribed to patients with chronic myeloid leukemia and Philadelphia-chromosome positive active lymphoblastic leukemia. Although, it has recently shown side effects causing blood clots and narrowing blood vessels.
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•FGFR plays a role in the signaling system with FGF by initiating signaling cascades that control development and tissue repair. The disruption of this signaling system is involved in tumor growth<ref name="one" />
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•While most inhibitors are selective for FGFR1-3 and show a reduced binding to FGFR4, Ponatinib binds to FGFR4<ref name="one" />
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•Ponatinib is a Bcr-Abl tyrosine kinase inhibitor (TKI)<ref name="one" />
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<scene name='48/483882/Secondary_structure/1'>Secondary Structure</scene>
<scene name='48/483882/Secondary_structure/1'>Secondary Structure</scene>

Revision as of 18:50, 7 April 2016


This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439.


Fibroblast Growth Factor Receptor/Ponatinib (4uxq) [1]

by Julie Boshar, Emily Boyle, Nicole Kirby, Cory Thomas, Connor Walsh

Student Projects for UMass Chemistry 423 Spring 2016

Fibroblast growth factor receptor in complex with ponatinib is a highly effective inhibitory treatment for chronic myeloid leukemia (4uxq)

Drag the structure with the mouse to rotate
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