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Introduction

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^[2]

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^[3]. Further, the drug is a Bcr-Abl tyrosine kinase inhibitor (TKI)^[4]. 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.

•Plays a role in a variety of cancers

•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.

•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^[5]

•While most inhibitors are selective for FGFR1-3 and show a reduced binding to FGFR4, Ponatinib binds to FGFR4^[6]

•Ponatinib is a Bcr-Abl tyrosine kinase inhibitor (TKI)^[7]

Overall Structure

•Ligands: SO4, 0LI [C29 H27 F3 N6 O]

•Identical amino acid sequence to cI44 with the exception of 1 residue.^[8]

secondary structure with two key residues in the activation loop (highlighted in light blue) for Ponatinab binding

Binding Interactions

•Ponatinib binds to the "DFG-out" conformation of Bcr-Abl, where the Phe (F) is out of its hydrophobic pocket^[9]

•To bind there must be a a conformational rearrangement of the conserved Asp630-Phe631-Gly632 (DFG) tripeptide motif at the proximal end of the activation loop^[10]

FGFR4 active site for ponatinib binding with involved residues labeled

Additional Features

• FGFR-4 is abundantly present in human prostate cancer

•Variant of FGFR-4 with (Arg(388)) replacing (Gly(388)) is associated with increased human prostate cancer. This causes increased receptor stability and activation. [2]

Quiz Question 1

See Also

• Fibroblast growth factor receptor
• 4uxq
• 4v01
• 4v04
• 4v05

Credits

Introduction - Emily & Cory

Overall Structure - Nicole & Connor

Drug Binding Site - Julie & Cory

Additional Features - Emily & Nicole

Quiz Question 1 - Julie & Connor

References

1. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
2. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
3. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
4. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
5. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
6. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
7. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
8. ↑ Ron D, Reich R, Chedid M, Lengel C, Cohen OE, Chan AM, Neufeld G, Miki T, Tronick SR. Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J Biol Chem. 1993 Mar 15;268(8):5388-94. PMID:7680645
9. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
10. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019

[1] Ron D, Reich R, Chedid M, Lengel C, Cohen OE, Chan AM, Neufeld G, Miki T, Tronick SR. Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J Biol Chem. 1993 Mar 15;268(8):5388-94. PMID:http://www.ncbi.nlm.nih.gov/pubmed/7680645

[2] Wang J, Yu W, Cai Y, Ren C, Ittmann MM. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia. 2008 Aug;10(8):847-56. PMID: http://www.ncbi.nlm.nih.gov/pubmed/18670643

[3] Tucker, J. A.; Klein, T.; Breed, J.; Breeze, A. L.; Overman, R.; Phillips, C.; Norman, R. A. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure 2014, 22, 1764-1774.