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 language | English (US) |
|---|---|
| Pages (from-to) | 2984-2992 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 114 |
| Issue number | 14 |
| DOIs | |
| State | Published - 2009 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)
AU - Zarrinkar, Patrick P.
AU - Gunawardane, Ruwanthi N.
AU - Cramer, Merryl D.
AU - Gardner, Michael F.
AU - Brigham, Daniel
AU - Belli, Barbara
AU - Karaman, Mazen W.
AU - Pratz, Keith
AU - Pallares, Gabriel
AU - Chao, Qi
AU - Sprankle, Kelly G.
AU - Patel, Hitesh K.
AU - Levis, Mark J
AU - Armstrong, Robert C.
AU - James, Joyce
AU - Bhagwat, Shripad S.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=70449475105&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-05-222034
DO - 10.1182/blood-2009-05-222034
M3 - Article
C2 - 19654408
AN - SCOPUS:70449475105
VL - 114
SP - 2984
EP - 2992
JO - Blood
JF - Blood
SN - 0006-4971
IS - 14
ER -