SKLB-D18 is an orally active ERK1/2/ERK5 inhibitor, with an IC50 of 38.69 nM and a K d of 126.9 nM against human ERK1, an IC50 of 40.12 nM and a K d of 209.8 nM against ERK2, and an IC50 of 59.72 nM and a K d of 468.2 nM against ERK5. SKLB-D18 inhibits cancer cell proliferation, induces G0/G1 cell cycle arrest and apoptosis. SKLB-D18 reduces the levels of p-ERK5, p-RSKp90, p-c-Myc and c-Myc, and upregulates the level of p-ERK1/2, thereby inhibiting the ERK1/2/5 pathway in cells. SKLB-D18 increases LC3B-II accumulation, and decreases the levels of p62, p-mTOR and p-p70S6K. SKLB-D18 elevates the levels of ROS, lipid peroxidation and free ferrous ions, reduces the levels of NCOA4 and GPX4, and induces ferritin autophagy -dependent ferroptosis in cancer cells. SKLB-D18 exhibits antitumor activity in a triple-negative breast cancer xenograft mouse model. SKLB-D18 can be used in research related to triple-negative breast cancer [1].
In Vivo, SKLB-D18 (25-50 mg/kg; p.o.; once daily; for 16 consecutive days) inhibits triple-negative breast cancer tumor growth in a dose-dependent manner in subcutaneous xenograft mouse models[1].
In Vitro, SKLB-D18 (1 μM) exhibits high selectivity for ERK1, ERK2 and ERK5, with inhibition rates of 96%, 94% and 83% respectively at the concentration of 1 μM[1]. SKLB-D18 (0-20 μM; 72 h) potently inhibits the proliferation of MDA-MB-231 (IC50 0.93 μM) and MDA-MB-468 (IC50 1.05 μM) in vitro, and this activity depends on the expression of ERK1/2/5[1]. SKLB-D18 (2 μM; 2 h) directly binds to ERK1/2 and ERK5 proteins in intact MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 24 h) reduces the levels of p-ERK5, p-RSKp90, p-c-Myc and c-Myc in a dose-dependent manner, while upregulating the level of p-ERK1/2, thereby inhibiting the ERK1/2/5 pathway in MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 14 days) potently and dose-dependently inhibits the long-term clonogenic proliferation of MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 24 h) induces dose-dependent G0/G1 cell cycle arrest in MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (0.5-2 μM; 16 h) potently and dose-dependently inhibits the migration of MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 24 h) activates complete autophagic flux in MDA-MB-231 and MDA-MB-468 cells by inhibiting the mTOR/p70S6K pathway. After 24 h of treatment, increased accumulation of LC3B-II, and decreased levels of p62, p-mTOR and p-p70S6K are observed[1]. SKLB-D18 (1-5 μM; 24 h) induces ferritinophagy-dependent ferroptosis in MDA-MB-231 and MDA-MB-468 cells by increasing the levels of ROS, lipid peroxidation and free ferrous ions, and decreasing the levels of NCOA4 and GPX4[1].
References:
[1]. Xiao H, et al. A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy. Signal Transduct Target Ther. 2025;10(1):70. Published 2025 Feb 20.
In Vivo, SKLB-D18 (25-50 mg/kg; p.o.; once daily; for 16 consecutive days) inhibits triple-negative breast cancer tumor growth in a dose-dependent manner in subcutaneous xenograft mouse models[1].
In Vitro, SKLB-D18 (1 μM) exhibits high selectivity for ERK1, ERK2 and ERK5, with inhibition rates of 96%, 94% and 83% respectively at the concentration of 1 μM[1]. SKLB-D18 (0-20 μM; 72 h) potently inhibits the proliferation of MDA-MB-231 (IC50 0.93 μM) and MDA-MB-468 (IC50 1.05 μM) in vitro, and this activity depends on the expression of ERK1/2/5[1]. SKLB-D18 (2 μM; 2 h) directly binds to ERK1/2 and ERK5 proteins in intact MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 24 h) reduces the levels of p-ERK5, p-RSKp90, p-c-Myc and c-Myc in a dose-dependent manner, while upregulating the level of p-ERK1/2, thereby inhibiting the ERK1/2/5 pathway in MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 14 days) potently and dose-dependently inhibits the long-term clonogenic proliferation of MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 24 h) induces dose-dependent G0/G1 cell cycle arrest in MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (0.5-2 μM; 16 h) potently and dose-dependently inhibits the migration of MDA-MB-231 and MDA-MB-468 cells[1]. SKLB-D18 (1-5 μM; 24 h) activates complete autophagic flux in MDA-MB-231 and MDA-MB-468 cells by inhibiting the mTOR/p70S6K pathway. After 24 h of treatment, increased accumulation of LC3B-II, and decreased levels of p62, p-mTOR and p-p70S6K are observed[1]. SKLB-D18 (1-5 μM; 24 h) induces ferritinophagy-dependent ferroptosis in MDA-MB-231 and MDA-MB-468 cells by increasing the levels of ROS, lipid peroxidation and free ferrous ions, and decreasing the levels of NCOA4 and GPX4[1].
References:
[1]. Xiao H, et al. A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy. Signal Transduct Target Ther. 2025;10(1):70. Published 2025 Feb 20.