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 W. Pratz; Gabriel Pallares; Qi Chao; Kelly G. Sprankle; Hitesh K. Patel; Mark Levis; Robert C. Armstrong; Joyce James; Shripad S. Bhagwat

doi:10.1182/blood-2009-05-222034

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 W. Pratz, Gabriel Pallares, Qi Chao, Kelly G. Sprankle, Hitesh K. Patel, Mark Levis, Robert C. Armstrong, Joyce James, Shripad S. Bhagwat

School of Medicine

Research output: Contribution to journal › Article › peer-review

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	https://doi.org/10.1182/blood-2009-05-222034
State	Published - 2009

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Zarrinkar, P. P., Gunawardane, R. N., Cramer, M. D., Gardner, M. F., Brigham, D., Belli, B., Karaman, M. W., Pratz, K. W., Pallares, G., Chao, Q., Sprankle, K. G., Patel, H. K., Levis, M., Armstrong, R. C., James, J., & 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 W.; Pallares, Gabriel; Chao, Qi; Sprankle, Kelly G.; Patel, Hitesh K.; Levis, Mark; Armstrong, Robert C.; James, Joyce; Bhagwat, Shripad S.

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

Research output: Contribution to journal › Article › peer-review

Zarrinkar, PP, Gunawardane, RN, Cramer, MD, Gardner, MF, Brigham, D, Belli, B, Karaman, MW, Pratz, KW, Pallares, G, Chao, Q, Sprankle, KG, Patel, HK, Levis, M, 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, Patrick P. ; Gunawardane, Ruwanthi N. ; Cramer, Merryl D. ; Gardner, Michael F. ; Brigham, Daniel ; Belli, Barbara ; Karaman, Mazen W. ; Pratz, Keith W. ; Pallares, Gabriel ; Chao, Qi ; Sprankle, Kelly G. ; Patel, Hitesh K. ; Levis, Mark ; 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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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.",

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AU - Karaman, Mazen W.

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AU - Sprankle, Kelly G.

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AU - James, Joyce

AU - Bhagwat, Shripad S.

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