MELK-T1(JNJ-47117096) HCl

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.

IC50: 23 nM (MELK), 18 nM (Flt3)