title: Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia.
abstract: Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Simon
authors.initials: S
authors.lastname: Crumpler
authors.forename: Chongbo
authors.initials: C
authors.lastname: Sun
authors.forename: Sian
authors.initials: S
authors.lastname: Avery
authors.forename: Butrus
authors.initials: B
authors.lastname: Atrash
authors.forename: Amir
authors.initials: A
authors.lastname: Faisal
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Moore
authors.forename: Magda
authors.initials: M
authors.lastname: Kosmopoulou
authors.forename: Nathan
authors.initials: N
authors.lastname: Brown
authors.forename: Peter W
authors.initials: PW
authors.lastname: Sheldrake
authors.forename: Katherine
authors.initials: K
authors.lastname: Bush
authors.forename: Alan
authors.initials: A
authors.lastname: Henley
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Richard
authors.initials: R
authors.lastname: Bayliss
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001682:Biological Availability; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C577926:6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo(4,5-b)pyridine; D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576920:Aurka protein, rat; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases