Quizartinib: Difference between revisions

Quizartinib
Names
	IUPAC name 1-(5-(tert-Butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea
	Other names AC220
Identifiers
CAS Number	950769-58-1 ;
3D model (JSmol)	Interactive image;
ChemSpider	24640357 ;
CompTox Dashboard (EPA)	DTXSID70241746 ;
	InChI InChI=1S/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36) Key: CVWXJKQAOSCOAB-UHFFFAOYSA-N ; InChI=1/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36) Key: CVWXJKQAOSCOAB-UHFFFAOYAF;
	SMILES CC(C)(C)c1cc(no1)NC(=O)Nc2ccc(cc2)c3cn4c5ccc(cc5sc4n3)OCCN6CCOCC6;
Properties
Chemical formula	C29H32N6O4S
Molar mass	560.67 g·mol−1
Density	1.4±0.1 g/cm3
Solubility in water	33.2mg/mL in DMSO
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

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Quizartinib (AC220) is a small molecule receptor tyrosine kinase inhibitor that is currently under development by Ambit Biosciences for the treatment of acute myeloid leukaemia. Its molecular target is FLT3, also known as CD135 which is a proto-oncogene.^[2]

Flt3 mutations are among the most common mutations in acute myeloid leukaemia due to internal tandem duplication of Flt3. The presence of this mutation is a marker of adverse outcome.

Biological Activity

Quizartinib (AC220) is a second-generation FLT3 inhibitor for Flt3(ITD/WT) with IC50 of 1.1 nM/4.2 nM, 10-fold more selective for Flt3 than KIT, PDGFRα, PDGFRβ,RET, and CSF-1R.

In vitro

AC220, a unique, potent and selective inhibitor of FLT3, has high affinity for FLT3 with a Kd value of 1.6 nM. AC220 inhibits the autophosphorylation of FLT3 in the human leukemia cell lines MV4-11 which harbor a homozygous FLT3-ITD mutation and is FLT3 dependent, and RS4;11 which expresses wild-type FLT3 with IC50 values of 1.1 nM and 4.2 nM, respectively. AC220 is the most potent cellular FLT3-ITD inhibitor, leading to the most significant inhibition of MV4-11 cell proliferation with IC50 of 0.56 nM compared to all other FLT3 inhibitors whose IC50 values range from 0.87 nM to 64 nM. AC220 has no inhibitory activity against the proliferation of A375 cells which harbor an activating mutation in BRAF and are not FLT3 dependent, indicating a large window between FLT3 inhibition and general cytotoxic effects^[3].

In vivo

Oral administration of AC220 (10 mg/kg) induces time-dependent inhibition of FLT3 autophosphorylation in the FLT3-ITD–dependent MV4-11 tumor xenograft mouse model; the inhibition being 90% at 2 hours and 40% at 24 hours. AC220 significantly extends survival in a mouse model of FLT3-ITD AML with doses as low as 1 mg/kg given orally once a day. Treatment with AC220 at 10 mg/kg for 28 days results in rapid and complete regression of tumors in all mice with no tumor regrowth during the 60-day posttreatment period. AC220 displays more significant efficacy compared to sunitinib treatment which causes tumors to shrink slowly and resume growth immediately upon discontinuation of treatment in all but one of the mice.

Mechanism

Specifically, Quizartinib selectively inhibits class III receptor tyrosine kinases, including FMS-related tyrosine kinase 3 (FLT3/STK1), colony-stimulating factor 1 receptor (CSF1R/FMS), stem cell factor receptor (SCFR/KIT), and platelet derived growth factor receptors (PDGFRs).^{[citation needed]}

Mutations cause constitutive action of Flt3 leading to resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.^{[citation needed]}

Clinical trials

It had good results in a phase II clinical trial for refractory AML - particularly in patients who went on to have a stem cell transplant.^[4].It shows unprecedented activity to recurrent and refractory AML and is said to be the first and only one single drug to make FLT3 internal tandem duplication and that AML patient can gain clinical benefit from.
In April 2014,a Phase III clinical trial for AML was sponsored by Ambit Biosciences Corporation.

References

^ http://www.chemspider.com/Chemical-Structure.24640357.html?rid=e3252a47-a43e-4f15-b0a6-d92d53a54b69
^ {{cite journal | author = Chao, Qi; Sprankle, Kelly G.; Grotzfeld, Robert M.; Lai, Andiliy G.; Carter, Todd A.; Velasco, Anne Marie; Gunawardane, Ruwanthi N.; Cramer, Merryl D.; Gardner, Michael F.; James, Joyce; Zarrinkar, Patrick P.; Patel, Hitesh K.; Bhagwat, Shripad S. | title = Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor | journal = Journal of Medicinal Chemistry | year = 2009 | volume = 52 | issue = 23 | pages = 7808–7816 | doi=10.1021/jm9007533}}
^ http://www.selleckchem.com/products/AC-220.html
^ Drug Tames Refractory AML. ASH Dec 2012

[1] ttp://www.chemspider.com/Chemical-Structure.24640357.html?rid=e3252a47-a43e-4f15-b0a6-d92d53a54b69

[2] {{cite journal | author = Chao, Qi; Sprankle, Kelly G.; Grotzfeld, Robert M.; Lai, Andiliy G.; Carter, Todd A.; Velasco, Anne Marie; Gunawardane, Ruwanthi N.; Cramer, Merryl D.; Gardner, Michael F.; James, Joyce; Zarrinkar, Patrick P.; Patel, Hitesh K.; Bhagwat, Shripad S. | title = Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor | journal = Journal of Medicinal Chemistry | year = 2009 | volume = 52 | issue = 23 | pages = 7808–7816 | doi=10.1021/jm9007533}}

[3] ttp://www.selleckchem.com/products/AC-220.html

[ASH2012-4] Drug Tames Refractory AML. ASH Dec 2012

[1]

[2]

[3]

[4]

@@ Line 25: / Line 25: @@
 |  C=29 |H=32 |N=6 |O=4 |S=1
 |  Appearance =
+|  Density = 1.4±0.1 g/cm3<ref>http://www.chemspider.com/Chemical-Structure.24640357.html?rid=e3252a47-a43e-4f15-b0a6-d92d53a54b69</ref>
-|  Density =
 |  MeltingPt =
 |  BoilingPt =
-|  Solubility = }}
+|  Solubility = 33.2mg/mL in DMSO }}
 | Section3 = {{Chembox Hazards
 |  MainHazards =
@@ Line 52: / Line 52: @@
 '''Quizartinib''' (AC220) is a small molecule [[receptor tyrosine kinase]] inhibitor that is currently under development by [[Ambit Biosciences]] for the treatment of [[acute myeloid leukaemia]]. Its molecular target is [[FLT3]], also known as CD135 which is a [[proto-oncogene]].<ref>{{cite journal | author = Chao, Qi; Sprankle, Kelly G.; Grotzfeld, Robert M.; Lai, Andiliy G.; Carter, Todd A.; Velasco, Anne Marie; Gunawardane, Ruwanthi N.; Cramer, Merryl D.; Gardner, Michael F.; James, Joyce; Zarrinkar, Patrick P.; Patel, Hitesh K.; Bhagwat, Shripad S.  | title = Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor | journal = Journal of Medicinal Chemistry | year = 2009 | volume = 52 | issue = 23 | pages = 7808–7816 | doi=10.1021/jm9007533}}</ref>
-Flt3 mutations are among the most common mutations in [[acute myeloid leukaemia]] due to [[internal tandem duplication]] of Flt3. The presence of this mutation is a marker of adverse outcome.
+Flt3 mutations are among the most common mutations in [[acute myeloid leukaemia]] due to internal tandem duplication of Flt3. The presence of this mutation is a marker of adverse outcome.
+==Biological Activity==
+Quizartinib (AC220) is a second-generation FLT3 inhibitor for Flt3(ITD/WT) with [[IC50]] of 1.1 nM/4.2 nM, 10-fold more selective for Flt3 than KIT, [[PDGFRα]], [[PDGFRβ]],[[ RET]], and CSF-1R.
+===In vitro===
+AC220, a unique, potent and selective inhibitor of FLT3, has high affinity for FLT3 with a Kd value of 1.6 nM. AC220 inhibits the [[autophosphorylation]] of FLT3 in the human [[leukemia]] cell lines MV4-11 which harbor a homozygous FLT3-ITD mutation and is FLT3 dependent, and RS4;11 which expresses wild-type FLT3 with IC50 values of 1.1 nM and 4.2 nM, respectively. AC220 is the most potent cellular FLT3-ITD inhibitor, leading to the most significant inhibition of MV4-11 cell proliferation with IC50 of 0.56 nM compared to all other FLT3 inhibitors whose IC50 values range from 0.87 nM to 64 nM. AC220 has no inhibitory activity against the proliferation of A375 cells which harbor an activating mutation in BRAF and are not FLT3 dependent, indicating a large window between FLT3 inhibition and general cytotoxic effects<ref>http://www.selleckchem.com/products/AC-220.html</ref>.
+===In vivo===
+Oral administration of AC220 (10 mg/kg) induces time-dependent inhibition of FLT3 [[autophosphorylation]] in the FLT3-ITD–dependent MV4-11 tumor xenograft mouse model; the inhibition being 90% at 2 hours and 40% at 24 hours. AC220 significantly extends survival in a mouse model of FLT3-ITD AML with doses as low as 1 mg/kg given orally once a day. Treatment with AC220 at 10 mg/kg for 28 days results in rapid and complete regression of tumors in all mice with no tumor regrowth during the 60-day posttreatment period. AC220 displays more significant efficacy compared to [[sunitinib]] treatment which causes tumors to shrink slowly and resume growth immediately upon discontinuation of treatment in all but one of the mice.
 ==Mechanism==
@@ Line 60: / Line 67: @@
 ==Clinical trials==
-It had good results in a phase II clinical trial for refractory AML - particularly in patients who went on to have a stem cell transplant.<ref name=ASH2012>[http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36351 Drug Tames Refractory AML. ASH Dec 2012]</ref>
+It had good results in a phase II clinical trial for refractory AML - particularly in patients who went on to have a stem cell transplant.<ref name=ASH2012>[http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36351 Drug Tames Refractory AML. ASH Dec 2012]</ref>.It shows unprecedented activity to recurrent and refractory AML and is said to be the first and only one single drug to make FLT3 internal tandem duplication and that AML patient can gain clinical benefit from.<br />
+In April 2014,a Phase III clinical trial for AML was sponsored by Ambit Biosciences Corporation.
 ==References==
 {{reflist}}