AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).
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.
Zarrinkar
Patrick P
PP
Ambit Biosciences, San Diego, CA 92121, USA. pzarrinkar@ambitbio.com
Gunawardane
Ruwanthi N
RN
Cramer
Merryl D
MD
Gardner
Michael F
MF
Brigham
Daniel
D
Belli
Barbara
B
Karaman
Mazen W
MW
Pratz
Keith W
KW
Pallares
Gabriel
G
Chao
Qi
Q
Sprankle
Kelly G
KG
Patel
Hitesh K
HK
Levis
Mark
M
Armstrong
Robert C
RC
James
Joyce
J
Bhagwat
Shripad S
SS
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D052160:Benzothiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005663:Furans; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D025941:Protein Interaction Mapping; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D000077157:Sorafenib; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D001557:Benzenesulfonates; D052160:Benzothiazoles; D002227:Carbazoles; D005663:Furans; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; C544967:quizartinib; D000077157:Sorafenib; C119379:lestaurtinib; C464670:tandutinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin