Quizartinib

Quizartinib
Names
Preferred IUPAC name
N-(5-tert-Butyl-1,2-oxazol-3-yl)-N′-(4-{7-[2-(morpholin-4-yl)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea
Other names
AC220, Vanflyta
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
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) ☒N
    Key: CVWXJKQAOSCOAB-UHFFFAOYSA-N ☒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
Pharmacology
L01EX11 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Quizartinib (AC220) is a small molecule receptor tyrosine kinase inhibitor, originally from Ambit Biosciences and later acquired by Daiichi Sankyo, that is currently under development for the treatment of acute myeloid leukaemia. Quizartinib is sold under the brand name Vanflyta in Japan.[1] 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.

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).

Mutations cause constant activation of the FLT3 pathway resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.

Clinical trials

It reported good results in 2012 from a phase II clinical trial for refractory AML - particularly in patients who went on to have a stem cell transplant.[3]

As of 2017, it has completed five clinical trials, and another seven are active.[4]

References

  1. ↑ "Daiichi Sankyo Launches FLT3 Inhibitor VANFLYTA® in Japan for the Treatment of Patients with Relapsed/Refractory FLT3-ITD AML". Retrieved 16 February 2021.
  2. ↑ 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. (2009). "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 of Medicinal Chemistry. 52 (23): 7808–7816. doi:10.1021/jm9007533. PMID 19754199.
  3. ↑ Drug Tames Refractory AML. ASH Dec 2012
  4. ↑ Quizartinib studies
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