SKLB-D18 is a potent, selective, first-in-class inhibitor of extracellular-regulated kinase 1/2 (ERK1/2) ERK1/2 and ERK5 with IC50 of 38.69/ 40.12 / 59.72 nM respecitvely.
SKLB-D18 has a dissociation constant (Kd) of 126.9 nM, 209.8 nM and 468.2 nM for ERK1/2/5, respectively, in isothermal titration calorimetry (ITC) assays.
SKLB-D18 inhibits TNBC cells viability in a dose-dependent manner, with potent anti-tumor activity against MDA-MB-231 (IC50 = 0.93 ± 0.11 μM) and MDA-MB-468 cells (IC50 = 1.05 ± 0.13 μM) than MDA-MB-436 (IC50 = 2.31 ± 0.29 μM) and BT549 cells (IC50 = 3.21 ± 0.34 μM).
SKLB-D18 shows high selectivity for ERK1/2 and ERK5 on 380 kinases using the DiscoveRx platform.
SKLB-D18 targets the ERK1/2-ERK5 compensatory pathway thereby effectively impeding TNBC cell proliferation and metastasis in vitro.
SKLB-D18 activates mTOR/p70S6K-regulated intact autophagic flux in TNBC cells.
SKLB-D18 induces ferritinophagy in MDA-MB-231 and MDA-MB-468 cells.
SKLB-D18 (25 mg/kg and 50 mg/kg) retards tumor growth in MDA-MB-231 xenograft model.