Emerging FMS-like tyrosine kinase 3 inhibitors for the treatment of acute myelogenous leukemia

Expert Opinion on Emerging Drugs

Volumn 16, Issue 3, 2011, Pages 407-423

  Prescott, Hillary ^a   Kantarjian, Hagop ^a   Cortes, Jorge ^a   Ravandi, Farhad ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

acute myelogenous leukemia; FLT3; FLT3 inhibitor; FLT3 ITD

Indexed keywords

CD135 ANTIGEN; ENZYME INHIBITOR; FMS LIKE TYROSINE KINASE 3 INHIBITOR; LESTAURTINIB; MIDOSTAURIN; QUIZARTINIB; SORAFENIB; SUNITINIB; TANDUTINIB; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; DRUG MECHANISM; DRUG POTENCY; DRUG TARGETING; ENZYME ACTIVATION; ENZYME INHIBITION; GENE MUTATION; HUMAN; KARYOTYPE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGNOSIS; PUBLICATION; REVIEW;

ANIMALS; CLINICAL TRIALS AS TOPIC; DRUG EVALUATION, PRECLINICAL; FMS-LIKE TYROSINE KINASE 3; HUMANS; LEUKEMIA, MYELOID, ACUTE; MULTICENTER STUDIES AS TOPIC; PROTEIN KINASE INHIBITORS; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 80052015797     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728214.2011.568938     Document Type: Review

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99. Chao Q, Sprankle KG, Grotzfeld RM, et al. Identification of N-(5-tert-butylisoxazol- 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. J Med Chem 2009;52:7808-16
100. Cortes J, Foran J, Ghirdaladze D, et al. AC220, a potent, selective, second generation FLT3 receptor tyrosine kinase (RTK) inhibitor, in a first-in-human (FIH) phase 1 AML study. Blood 2009;114:abstract 636 This Phase I study described the PK characteristics of AC220, determined the MTD for future studies, and demonstrated ACC 220 to produce response rates in refractory AML patients.
101. James J, Pratz K, Stine A, et al. Clinical pharmacokinetics and FLT3 phosphorylation of AC220, a highly potent and selective inhibitor of FLT3. Blood 2008;112:abstract 2637
102. Belli BA, Dao A, Bhagwat S, et al. AC220, a potent and specific FLT3 inhibitor, enhances the cytotoxic effects of chemotherapeutic agents in cell culture and in mouse tumor xenografts. Blood 2009;114:abstract 2052
103. Brigham D, Belli BA, Breider M, et al. AC220, a FLT3 inhibitor, increases survival in two genotypically distinct FLT3-ITD models of acute myeloid leukemia and provides sustained protection following chronic administration. Blood 2009;114:abstract 2053
104. Piloto O, Wright M, Brown P, et al. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 2007;109:1643-52
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106. Pratz KW, Sato T, Murphy KM, et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 2010;115:1425-32 This study highlights the significance of FLT3-mutant allelic burden and clinical status on response to FLT3 inhibitors; high mutant allelic burden and patients with relapsed disease were associated with higher response to cytotoxicity with FLT3 inhibitors. It also provides important information on the relationship between FLT3 inhibitor selectivity and response to treatment.