Identification And Development Of 1,4-diaryl-1,2,3-triazolo-based Ureas As Novel FLT3 Inhibitors

Acute myeloid leukemia(AML)is a hematopoietic malignancy characterized by aberrant and rapid proliferation of hematopoietic cells in the bone marrow and blood,leading to the accumulation of abnormally functioning white blood cells.Studies show that most AML patients have underlying genetic mutations.FLT3-ITD mutations,which consist of internal tandem duplications in the juxtamembrane domain of FLT3(FMS-like tyrosine kinase 3)are present in 25% of all AML patients and are frequently associated with adverse clinical outcome.Therefore,FLT3-ITD is a promising target for the treatment of AML.A series of diaryl ureas were identified as potent and selective FLT3 inhibitors by Ambit Biosciences in 2009,on the basis of this report,a class of triazolo-based ureas were designed and synthesized as novel FLT3 inhibitors in our group.Many of these compounds displayed potent activity against Ba F3-FLT3-ITD cells and FLT3-ITD positive AML cells MV4-11.Structure-activity relationship studies led to the discovery of compound CQ032,which exhibited the best potency against Ba F3-FLT3-ITD cells and MV4-11 cells.It also exhibited high selectivity over FLT3 wt cell lines such as U937 and HL60,and good selectivity for a panel of 468 kinases.The FLT3 inhibitory effect of compound CQ032 was shown that it can dose-dependently inhibited the phosphorylation of FLT3 and downstream signaling proteins and induced G0/G1 cell cycle arrested and apoptosis in MV4-11 cells.In vivo evaluation,CQ032 displayed suitable pharmacokinetic properties(F=35.81%)and strong in vivo antitumor activity.It may serve as a potential drug candidate for FLT3-ITD positive AML.Meanwhile,a novel and simple Boulton-Katrizky-type rearrangement reaction was reported.A vareity of 1-(isoxazol-3-yl)-3-arylureas were transformed into 5-(2-oxoalkyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones under basic conditions.A one-pot reaction was also developed through simple isoxazol-3-amines with phenyl isocyanates to provide the desired rearrangement products,with prolonged time the oxidized side products could be formed in these reactions.