Dasatinib: Difference between revisions
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< | <StructureSection load='' size='450' side='right' scene='Dasatinib/Dasatinib/1' caption='Dasatinib, also known as Sprycel ([[2gqg]])'> | ||
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===Better Known as: Sprycel=== | ===Better Known as: Sprycel=== | ||
* Marketed By: Bristol-Myers Squibb | * Marketed By: Bristol-Myers Squibb | ||
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===Mechanism of Action=== | ===Mechanism of Action=== | ||
Chronic Myelogenous [[Cancer|Leukemia]] (CML) results from a gene defect in a haematological stem cell, <scene name='Dasatinib/Abl/2'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. | Chronic Myelogenous [[Cancer|Leukemia]] (CML) results from a gene defect in a haematological stem cell, <scene name='Dasatinib/Abl/2'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. | ||
Dasatinib functions by binding in the ATP site of the active conformation of BCR-Abl. This is unique as Abl inhibitors like [[Imatinib]] and [[Nilotinib]] bind only the inactive conformation. The well known <scene name=' | Dasatinib functions by binding in the ATP site of the active conformation of BCR-Abl. This is unique as Abl inhibitors like [[Imatinib]] and [[Nilotinib]] bind only the inactive conformation. The well known <scene name='43/430079/Cv/1'>"DFG triad" is in the "in" conformation</scene> in the Dasatinib bound BCR-Abl, with the so-called <scene name='Dasatinib/Activation/3'>activation loop </scene> extending away from the ATP binding site & <scene name='Dasatinib/P_loop/2'>P-loop</scene> covering the top of the ATP binding site. A critically important residue, Thr 315, is known as <scene name='Dasatinib/315/2'>the gatekeeper residue</scene>, forms a <scene name='Dasatinib/Site/4'>hydrogen bond with Dasatinib</scene>. In other kinases like B-Raf, p38 & KDR, position 315 is occupied by a larger residue that is not conducive to Dasatinib binding, giving Dasatinib its high specificity.<ref>PMID:17164530</ref> A number of point mutations within BCR-Abl result in Imatinib resistance. There are 15 well known Imatinib resistance conferring mutations at positions like 244, 250, 252, 253, 315, 317, 351, and 396. Dasatinib has shown effectiveness with nearly all Imatinib resistant versions of BCR-Abl, with the exception of the T315I/A & T317L/V mutants. <ref>PMID:16172030</ref> In BCR-Abl, <scene name='Dasatinib/Binding/1'>Dasatinib is bound</scene> by H-bonds to residues Met 318 an Thr 315, along with hydrophobic interactions with residues Ala 380, Leu 370, Met 290, Gly 321, Thr 319, Ala 269, Phe 317, Glu 316, Lys 271, Ile 313, Val 299 & Glu 286, stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref><ref>PMID:16740718</ref> | ||
To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>. | |||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> | <table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> | ||
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</tr> | </tr> | ||
</table> | </table> | ||
</StructureSection> | |||
===References=== | ===References=== | ||
<references/> | <references/> | ||
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Latest revision as of 14:15, 18 January 2017
Better Known as: Sprycel
Mechanism of ActionChronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, . Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Dasatinib functions by binding in the ATP site of the active conformation of BCR-Abl. This is unique as Abl inhibitors like Imatinib and Nilotinib bind only the inactive conformation. The well known in the Dasatinib bound BCR-Abl, with the so-called extending away from the ATP binding site & covering the top of the ATP binding site. A critically important residue, Thr 315, is known as , forms a . In other kinases like B-Raf, p38 & KDR, position 315 is occupied by a larger residue that is not conducive to Dasatinib binding, giving Dasatinib its high specificity.[2] A number of point mutations within BCR-Abl result in Imatinib resistance. There are 15 well known Imatinib resistance conferring mutations at positions like 244, 250, 252, 253, 315, 317, 351, and 396. Dasatinib has shown effectiveness with nearly all Imatinib resistant versions of BCR-Abl, with the exception of the T315I/A & T317L/V mutants. [3] In BCR-Abl, by H-bonds to residues Met 318 an Thr 315, along with hydrophobic interactions with residues Ala 380, Leu 370, Met 290, Gly 321, Thr 319, Ala 269, Phe 317, Glu 316, Lys 271, Ile 313, Val 299 & Glu 286, stabilizing the inhibited conformation of the kinase.[4][5] To see of key structural elements Click: , , & the . Pharmacokinetics
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References
- ↑ Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. PMID:16775234 doi:10.1056/NEJMoa055229
- ↑ Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):80-93. Epub 2006, Dec 13. PMID:17164530 doi:http://dx.doi.org/10.1107/S0907444906047287
- ↑ Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta. 2005 Dec 30;1754(1-2):3-13. Epub 2005 Sep 8. PMID:16172030 doi:10.1016/j.bbapap.2005.07.040
- ↑ Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):80-93. Epub 2006, Dec 13. PMID:17164530 doi:http://dx.doi.org/10.1107/S0907444906047287
- ↑ Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE, Kish K, Lee FY, Borzillerri R, Lombardo LJ, Xie D, Zhang Y, Klei HE. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006 Jun 1;66(11):5790-7. PMID:16740718 doi:66/11/5790