MELK-T1(JNJ-47117096) HCl is potent and selective MELK inhibitor, with an IC 50 of 23 nM, also effectively inhibits Flt3, with an IC 50 of 18 nM, and slighitly blocks CAMKIIδ, Mnk2, CAMKIIγ, and MLCK (IC 50 , 810 nM, 760 nM, 1000 nM, 1000 nM). It suppresses the proliferation of Flt3 -driven Ba/F3 cell lines, with an IC 50 of 1.5 μM in the absence of IL-3, while no inhibitory activity is observed in the presence of IL-3. It does not inhibit the proliferation of Ba/F3 cell lines transfected with either FGFR1, FGFR3, or KDR, either in the presence or absence of IL-3. JNJ-47117096 (MELK-T1, 10 μM) delays the progression of MCF-7 cells through S -phase. JNJ-47117096 inhibits MELK, and then exerts stalled replication forks and DNA double-strand breaks (DSBs). JNJ-47117096 activates the ATM-mediated DNA-damage response (DDR). JNJ-47117096 (3, 10 μM) results in a growth arrest and a senescent phenotype. Moreover, JNJ-47117096 induces a strong phosphorylation of p53, a prolonged up-regulation of p21 and a down-regulation of FOXM1 target genes.
