Jeong, P; Moon, Y; Lee, JH; Lee, SD; Park, J; Lee, J; Kim, J; Lee, HJ; Kim, NY; Choi, J; Heo, JD; Shin, JE; Park, HW; Kim, YG; Han, SY; Kim, YC
FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC50 values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI50 value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib. © 2020 Elsevier Masson SAS
3 [(2 aminoethoxy)imino] 5 hydroxy 5' nitro [2,3' biindolinylidene] 2' one; 3 [(2 aminoethoxy)imino] 5 hydroxy 5' nitro [2,3' biindolinylidene] 2' one one; 3 [(2 bromoethoxy)imino] 5 hydroxy 5' nitro [2,3' biindolinylidene] 2' one; 3 [(2 bromoethoxy)imino] 5' (trifluoromethoxy) [2,3' biindolinylidene] 2' one; 3 [(2 bromoethoxy)imino] 5' fluoro [2,3' biindolinylidene] 2' one; 3 [(2 bromoethoxy)imino] 5' methoxy [2,3' biindolinylidene] 2' one; 3 [(2 bromoethoxy)imino] 5' nitro [2,3' biindolinylidene] 2' one; 3 [(2 bromoethoxy)imino] 5,5' difluoro [2,3' biindolinylidene] 2' one; 3 [(2 bromoethoxy)imino] [2,3' biindolinylidene] 2' one; 3 [[2 (piperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5 fluoro 5' nitro 3 [[2 (piperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5 hydroxy 5' nitro 3 [[2 (piperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5' fluoro 3 [[2 (piperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5' nitro 3 [[2 (piperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene 2' one; 5,5' difluoro 3 [(2 morpholinoethoxy)imino] [2,3' biindolinylidene] 2' one; 5,5' difluoro 3 [[2 (4 methylpiperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5,5' difluoro 3 [[2 (piperazin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5,5' difluoro 3 [[2 (piperidin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5,5' difluoro 3 [[2 (piperidin 4 ylamino)ethoxy]imino] [2,3' biindolinylidene] 2' one; 5,5' difluoro 3 [[2 (pyrrolidin 1 yl)ethoxy]imino] [2,3' biindolinylidene] 2' one; antileukemic agent; crenolanib; gilteritinib; indirubin; indirubin 3' oxime derivative; oxime derivative; quizartinib; sorafenib; tert butyl [2 [[[ 5 hydroxy 5' nitro 2' oxo (2,3' biindolinylidene) 3 ylidene]amino]oxy]ethyl]carbamate; unclassified drug; unindexed drug; antineoplastic agent; CD135 antigen; FLT3 protein, human; indirubin-3'-monoxime; indole derivative; oxime; protein kinase inhibitor; A-549 cell line; acute myeloid leukemia; adult; animal experiment; animal model; antineoplastic activity; antiproliferative activity; area under the curve; Article; cancer inhibition; controlled study; drug binding; drug bioavailability; drug clearance; drug conformation; drug half life; drug potency; drug selectivity; female; GI50; HCT 116 cell line; Hep-G2 cell line; human; human cell; IC50; in vitro study; in vivo study; K-562 cell line; male; maximum plasma concentration; MDA-MB-231 cell line; molecular docking; MOLM-14 cell line; mouse; MV4-11 cell line; nonhuman; PC-3 [Human prostate carcinoma] cell line; SK-OV-3 cell line; structure activity relation; tumor xenograft; acute myeloid leukemia; animal; chemistry; drug design; drug effect; drug screening; metabolism; oral drug administration; pathology; phosphorylation; protein conformation; tumor cell line; Administration, Oral; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; fms-Like Tyrosine Kinase 3; Humans; Indoles; Leukemia, Myeloid, Acute; Mice; Molecular Docking Simulation; Oximes; Phosphorylation; Protein Conformation; Protein Kinase Inhibitors; Structure-Activity Relationship; Xenograft Model Antitumor Assays