title: Identification of N-(5-tert-butyl-isoxazol-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.
abstract: 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.
authors.affiliation: Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, California 92121, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chao
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Sprankle
authors.forename: Robert M
authors.initials: RM
authors.lastname: Grotzfeld
authors.forename: Andiliy G
authors.initials: AG
authors.lastname: Lai
authors.forename: Todd A
authors.initials: TA
authors.lastname: Carter
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Velasco
authors.forename: Ruwanthi N
authors.initials: RN
authors.lastname: Gunawardane
authors.forename: Merryl D
authors.initials: MD
authors.lastname: Cramer
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Zarrinkar
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Patel
authors.forename: Shripad S
authors.initials: SS
authors.lastname: Bhagwat
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D052160:Benzothiazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3