AML is an aggressive and frequently fatal hematologic malignancy, which lacks for efficient therapeutics with tolerable side effects. We herein reported the design of novel kinase inhibitors as AURKA-selective, FLT3-selective, and dual AURKA/FLT3 inhibitors by fine-tuning appropriate substituent at certain positions of quinazoline-thiazole series. Further structure-activity relationship and computer modeling studies led to the identification of dual AURKA/FLT3 inhibitor 39 which exhibited both excellent enzyme activities (AURKA IC50 = 25 nM, FLT3 IC50 = 19 nM) as well as antiproliferative activities on MOLM-13 and MV4-11 cells, with an IC50 value of ~5 nM. More importantly, 39 potently inhibited AURKA and FLT3 exerted excellent in vivo efficacy not only in MOLM-13 but also MV4-11 xenograft models at a dose of 1 to 10 mg/kg, resulting in 39 as a preclinical development candidate with high potential for the treatment of AML.
Date:
2015-08
Relation:
Abstracts of Papers of the American Chemical Society. 2015 Aug;250:Meeting Abstract 490.
