Fms样酪氨酸激酶3
髓系白血病
奥西多尔
白血病
癌症研究
化学
髓样
细胞生长
对接(动物)
激酶
生物
突变
生物化学
遗传学
基因
医学
催化作用
护理部
作者
Onur Bender,Mai E. Shoman,Taha F. S. Ali,Rumeysa Dogan,Ismail Celik,Adriano Mollica,Mohammed I. A. Hamed,Omar M. Aly,Abdulwahab Alamri,Jowaher Alanazi,Nafees Ahemad,Siew Hua Gan,Jonaid Ahmad Malik,Sirajudheen Anwar,Arzu Atalay,Eman A. M. Beshr
标识
DOI:10.1002/ardp.202200407
摘要
FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a–c inhibited 68%–73% and 83%–91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%–2% and 27%–39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-β. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.
科研通智能强力驱动
Strongly Powered by AbleSci AI