AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)

Patrick P. Zarrinkar, Ruwanthi N. Gunawardane, Merryl D. Cramer, Michael F. Gardner, Daniel Brigham, Barbara Belli, Mazen W. Karaman, Keith Pratz, Gabriel Pallares, Qi Chao, Kelly G. Sprankle, Hitesh K. Patel, Mark J Levis, Robert C. Armstrong, Joyce James, Shripad S. Bhagwat

Research output: Contribution to journalArticle

Abstract

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.

Original languageEnglish (US)
Pages (from-to)2984-2992
Number of pages9
JournalBlood
Volume114
Issue number14
DOIs
StatePublished - 2009

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4'-N-benzoylstaurosporine
Pharmacokinetics
Receptor Protein-Tyrosine Kinases
Acute Myeloid Leukemia
Assays
Animals
Phosphotransferases
Animal Models
Mutation
Pharmaceutical Preparations
Therapeutics
lestaurtinib
sorafenib
sunitinib
tandutinib

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zarrinkar, P. P., Gunawardane, R. N., Cramer, M. D., Gardner, M. F., Brigham, D., Belli, B., ... Bhagwat, S. S. (2009). AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood, 114(14), 2984-2992. https://doi.org/10.1182/blood-2009-05-222034

AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). / Zarrinkar, Patrick P.; Gunawardane, Ruwanthi N.; Cramer, Merryl D.; Gardner, Michael F.; Brigham, Daniel; Belli, Barbara; Karaman, Mazen W.; Pratz, Keith; Pallares, Gabriel; Chao, Qi; Sprankle, Kelly G.; Patel, Hitesh K.; Levis, Mark J; Armstrong, Robert C.; James, Joyce; Bhagwat, Shripad S.

In: Blood, Vol. 114, No. 14, 2009, p. 2984-2992.

Research output: Contribution to journalArticle

Zarrinkar, PP, Gunawardane, RN, Cramer, MD, Gardner, MF, Brigham, D, Belli, B, Karaman, MW, Pratz, K, Pallares, G, Chao, Q, Sprankle, KG, Patel, HK, Levis, MJ, Armstrong, RC, James, J & Bhagwat, SS 2009, 'AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)', Blood, vol. 114, no. 14, pp. 2984-2992. https://doi.org/10.1182/blood-2009-05-222034
Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009;114(14):2984-2992. https://doi.org/10.1182/blood-2009-05-222034
Zarrinkar, Patrick P. ; Gunawardane, Ruwanthi N. ; Cramer, Merryl D. ; Gardner, Michael F. ; Brigham, Daniel ; Belli, Barbara ; Karaman, Mazen W. ; Pratz, Keith ; Pallares, Gabriel ; Chao, Qi ; Sprankle, Kelly G. ; Patel, Hitesh K. ; Levis, Mark J ; Armstrong, Robert C. ; James, Joyce ; Bhagwat, Shripad S. / AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). In: Blood. 2009 ; Vol. 114, No. 14. pp. 2984-2992.
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