Quizartinib

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
950769-58-1 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:90217 N
ChEMBL ChEMBL576982 N
ChemSpider 24640357 N
5658
UNII 7LA4O6Q0D3 YesY
Properties
C29H32N6O4S
Molar mass 560.67 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

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.[1]

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 constitutive action of Flt3 resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.

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.[2]

References

  1. ↑ 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.
  2. ↑ Drug Tames Refractory AML. ASH Dec 2012


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