Dasatinib: Difference between revisions

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New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="" align="right" caption="Dasatinib, also known as Sprycel ([[____]])"/> ===Better Known as: Sprycel=== * Marketed By: ...
 
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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="" align="right" caption="Dasatinib, also known as Sprycel ([[____]])"/>
<StructureSection load='' size='450' side='right' scene='Dasatinib/Dasatinib/1' caption='Dasatinib, also known as Sprycel ([[2gqg]])'>
__TOC__
===Better Known as: Sprycel===
===Better Known as: Sprycel===
* Marketed By: Bristol-Myers Squibb
* Marketed By: Bristol-Myers Squibb
* Major Indication: Chronic Myelogenous [[Cancer|Leukemia]] (CML)
* Major Indication: Chronic Myelogenous [[Cancer|Leukemia]] (CML)
* Drug Class: Receptor Tyrosine Kinase (Especially, PDGFR, KIT &  BCR-Abl) Inhibitor
* Drug Class: Receptor Tyrosine Kinase (Especially, PDGFR, KIT &  BCR-Abl) Inhibitor
* Date of FDA Approval (Expiration):  
* Date of FDA Approval (Expiration): 2006 (2020)
* Expected Sales in Combination with [[Imatinib]]:  
* 2009 Global Sales: $421 Million
* Importance:
* Importance: It is a second generation receptor Tyrosine kinase inhibitor. It binds to Abl with less stringent conformational requirements so it exhibits increased potency compared to [[Imatinib]] although with less selectivity. Unlike most RTK inhibitors, Dasatinib binds the active conformation of BCR-Abl. Is used to treat patients with certain Imatinib resistant forms of [[Cancer|CML]]. Controversial due to its nearly $50,000 per year cost.<ref>doi:10.1056/NEJMoa055229</ref>
* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders
* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders


===Mechanism of Action===
===Mechanism of Action===
Chronic Myelogenous [[Cancer|Leukemia]] (CML) results from a gene defect in a haematological stem cell, <scene name='Nilotinib/Bcr/1'>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. Nilotinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Nilotinib/Dfg/2'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Nilotinib/Gate/1'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Nilotinib/Gate/2'>Thr 315 shifts to allow binding of Nilotinib</scene>. In other kinases like B-Raf, p38 & KDR, position 315 is occupied by a larger residue that is not conducive to Nilotinib binding, giving Nilotinib its high specificity.<ref>PMID:17164530</ref> A number of point mutations within BCR-Abl result in [[Imatinib]] resistance. There are 33 well known Imatinib resistance conferring mutations at positions like 244, 250, 252, 253, 315, 317, 351, and 396. Nilotinib has shown effectiveness with nearly all Imatinib resistant versions of BCR-Abl, with the exception of the T315I mutant. <ref>PMID:16172030</ref> In BCR-Abl, <scene name='Nilotinib/Binding/2'>Nilotinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, along with hydrophobic interactions with residues HIs 361, Ile 293, Ala 380, Val 299, Met 290, Lys 271, & Ala 269, stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref><ref>PMID: 15710326</ref>
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='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>
</table>
</table>
 
</StructureSection>
===References===
===References===
<references/>
<references/>
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Latest revision as of 14:15, 18 January 2017

Better Known as: Sprycel

  • Marketed By: Bristol-Myers Squibb
  • Major Indication: Chronic Myelogenous Leukemia (CML)
  • Drug Class: Receptor Tyrosine Kinase (Especially, PDGFR, KIT & BCR-Abl) Inhibitor
  • Date of FDA Approval (Expiration): 2006 (2020)
  • 2009 Global Sales: $421 Million
  • Importance: It is a second generation receptor Tyrosine kinase inhibitor. It binds to Abl with less stringent conformational requirements so it exhibits increased potency compared to Imatinib although with less selectivity. Unlike most RTK inhibitors, Dasatinib binds the active conformation of BCR-Abl. Is used to treat patients with certain Imatinib resistant forms of CML. Controversial due to its nearly $50,000 per year cost.[1]
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Chronic 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

Tyrosine Kinase Inhibitor Pharmacokinetics
VEGFR & KIT Inhibitors EGFR Inhibitors BCR-Abl Inhibitor
Parameter Sunitinib
(Sutent) 		Sorafenib
(Nexavar) 		Erlotinib
(Tarceva) 		Gefitinib
(Iressa) 		Lapatinib
(Tykerb) 		Imatinib
(Gleevec) 		Nilotinib
(Tasigna) 		Dasatinib
(Sprycel)
Tmax (hr) 8 8.3 2.0 5.4 4 3.7 3.0 1.0
Cmax (ng/ml) 24.6 460 69.6 130 115 2070 411 124
Bioavailability (%) Variable 29-49 99 59 Variable 98 30 20
Protein Binding (%) 95 99 93 90 99 95 98 96
T1/2 (hr) 83 29 9.4 26.9 9.6 26.6 16.0 3.3
AUC (ng/ml/hr) 1921 11040 20577 3850 1429 4760 10052 461
Dosage (mg) 50 50 150 250 100 400 200 200
Metabolism Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4)

For Pharmacokinetic Data References, see: References

Dasatinib, also known as Sprycel (2gqg)

Drag the structure with the mouse to rotate

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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

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