su-11248 and quizartinib

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.

Topics: Animals; Benzenesulfonates; Benzothiazoles; Bone Marrow; Carbazoles; Cell Line, Tumor; Cell Proliferation; Female; fms-Like Tyrosine Kinase 3; Furans; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Nude; Mice, SCID; Niacinamide; Phenylurea Compounds; Phosphorylation; Piperazines; Prognosis; Protein Interaction Mapping; Protein Kinase C; Protein Kinase Inhibitors; Pyridines; Quinazolines; Sorafenib; Staurosporine; Xenograft Model Antitumor Assays

Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.

Topics: Animals; Benzothiazoles; Cell Line, Tumor; Drug Evaluation, Preclinical; Female; fms-Like Tyrosine Kinase 3; Humans; Male; Mice; Phenylurea Compounds; Protein Kinase Inhibitors; Rats; Solubility; Substrate Specificity; Xenograft Model Antitumor Assays