SL-176 is a PPM1D ( Wip1 ) inhibitor. SL-176 inhibits lipid droplet formation, downregulates the mRNA and protein expression of PPARγ and C/EBPα, and blocks adipocyte differentiation. SL-176 induces G2/M cell cycle arrest, apoptosis and inhibits cell proliferation in breast cancer cells overexpressing PPM1D, and activates components of the p53 pathway. SL-176 suppresses tumor growth in a zebrafish model of neuroblastoma. SL-176 is applicable to research related to obesity, breast cancer and neuroblastoma [1] [2] [3].
In Vivo, SL-176 (10 μM; added to water; continuous exposure; 72 hours) in combination with 1 μM GSK-J4 significantly reduces neuroblastoma tumor growth in zebrafish xenografts, with a mean percent change in tumor size that is significantly lower than vehicle control (P = 0.0096)[3].
In Vitro, SL-176 potently inhibits the phosphatase activity of mouse PPM1D, with an IC50 of 112 nM[1]. SL-176 (0-15 μM, 8 days) inhibits lipid droplet formation in 3T3-L1 cells in a dose-dependent manner. At the concentration of 15 μM, it reduces the relative lipid content to 32% of that in the control group, decreases the average lipid droplet size in cells from 2.95 μm to 1.71 μm, and shifts the lipid droplet size distribution toward smaller sizes[1]. SL-176 (10 μM, 8 days) reduces the mRNA expression of PPARγ, C/EBPα and GLUT4 in 3T3-L1 cells, but has no effect on the mRNA expression of C/EBPβ[1]. SL-176 (0-15 μM, 8 days) reduces the protein expression of PPARγ1, PPARγ2 and C/EBPα in 3T3-L1 cells in a dose-dependent manner, but has no effect on the protein expression of C/EBPβ[1]. SL-176 potently and specifically inhibits the phosphatase activity of recombinant His-PPM1D (1-420) in a non-competitive manner, with an IC50 of 110 nM[2]. SL-176 (for 3 days) potently inhibits the proliferation of MCF-7 breast cancer cells overexpressing PPM1D, with an IC50 of 7.4 μM[2]. SL-176 (0-20 μM) exerts a selective inhibitory effect on the proliferation of p53-deficient, PPM1D-overexpressing H1299 (PMD-9) cells, with greater potency than that observed in parental H1299 cells with normal PPM1D expression[2]. SL-176 activates the p53 pathway in MCF-7 breast cancer cells by enhancing p53 Ser15 phosphorylation, and induces G2/M cell cycle arrest and apoptosis in these cells[2]. SL-176 (11 μM; 72 h) synergistically reduces the viability of IMR-32 and SK-N-AS neuroblastoma cells in combination with GSK-J4 [3]. Combination treatment with SL-176 (72 h) and GSK-J4 induces additive to synergistic cytotoxicity in all tested neuroblastoma cell lines (IMR-32, SK-N-SH, SK-N-AS, SK-N-BE (2), SK-N-FI, SK-N-DZ, Kelly, CHLA-20 cells)[3]. Combination treatment with SL-176 (7.5-15 μM; 6 days) and GSK-J4 reduces spheroid volume in a dose-dependent manner and induces apoptosis in 3D neuroblastoma spheroid models of IMR-32 and SK-N-AS[3]. Combination treatment with SL-176 (3-5 μM; 48-72 h) and GSK-J4 activates downstream targets of WIP1, upregulates the expression of p53 pathway genes, and increases the levels of apoptotic markers in IMR-32, SK-N-AS and SK-N-BE (2) neuroblastoma cells[3].
References:
[1]. Kamada R, et al. Inhibition of lipid droplet formation by Ser/Thr protein phosphatase PPM1D inhibitor, SL-176. PLoS One. 2019;14(2):e0212682. Published 2019 Feb 27.
[2]. Ogasawara S, et al. Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation. Bioorg Med Chem. 2015;23(19):6246-6249.
[3]. Treis D, et al. Targeted inhibition of WIP1 and histone H3K27 demethylase activity synergistically suppresses neuroblastoma growth. Cell Death Dis. 2025;16(1):318. Published 2025 Apr 19.
In Vivo, SL-176 (10 μM; added to water; continuous exposure; 72 hours) in combination with 1 μM GSK-J4 significantly reduces neuroblastoma tumor growth in zebrafish xenografts, with a mean percent change in tumor size that is significantly lower than vehicle control (P = 0.0096)[3].
In Vitro, SL-176 potently inhibits the phosphatase activity of mouse PPM1D, with an IC50 of 112 nM[1]. SL-176 (0-15 μM, 8 days) inhibits lipid droplet formation in 3T3-L1 cells in a dose-dependent manner. At the concentration of 15 μM, it reduces the relative lipid content to 32% of that in the control group, decreases the average lipid droplet size in cells from 2.95 μm to 1.71 μm, and shifts the lipid droplet size distribution toward smaller sizes[1]. SL-176 (10 μM, 8 days) reduces the mRNA expression of PPARγ, C/EBPα and GLUT4 in 3T3-L1 cells, but has no effect on the mRNA expression of C/EBPβ[1]. SL-176 (0-15 μM, 8 days) reduces the protein expression of PPARγ1, PPARγ2 and C/EBPα in 3T3-L1 cells in a dose-dependent manner, but has no effect on the protein expression of C/EBPβ[1]. SL-176 potently and specifically inhibits the phosphatase activity of recombinant His-PPM1D (1-420) in a non-competitive manner, with an IC50 of 110 nM[2]. SL-176 (for 3 days) potently inhibits the proliferation of MCF-7 breast cancer cells overexpressing PPM1D, with an IC50 of 7.4 μM[2]. SL-176 (0-20 μM) exerts a selective inhibitory effect on the proliferation of p53-deficient, PPM1D-overexpressing H1299 (PMD-9) cells, with greater potency than that observed in parental H1299 cells with normal PPM1D expression[2]. SL-176 activates the p53 pathway in MCF-7 breast cancer cells by enhancing p53 Ser15 phosphorylation, and induces G2/M cell cycle arrest and apoptosis in these cells[2]. SL-176 (11 μM; 72 h) synergistically reduces the viability of IMR-32 and SK-N-AS neuroblastoma cells in combination with GSK-J4 [3]. Combination treatment with SL-176 (72 h) and GSK-J4 induces additive to synergistic cytotoxicity in all tested neuroblastoma cell lines (IMR-32, SK-N-SH, SK-N-AS, SK-N-BE (2), SK-N-FI, SK-N-DZ, Kelly, CHLA-20 cells)[3]. Combination treatment with SL-176 (7.5-15 μM; 6 days) and GSK-J4 reduces spheroid volume in a dose-dependent manner and induces apoptosis in 3D neuroblastoma spheroid models of IMR-32 and SK-N-AS[3]. Combination treatment with SL-176 (3-5 μM; 48-72 h) and GSK-J4 activates downstream targets of WIP1, upregulates the expression of p53 pathway genes, and increases the levels of apoptotic markers in IMR-32, SK-N-AS and SK-N-BE (2) neuroblastoma cells[3].
References:
[1]. Kamada R, et al. Inhibition of lipid droplet formation by Ser/Thr protein phosphatase PPM1D inhibitor, SL-176. PLoS One. 2019;14(2):e0212682. Published 2019 Feb 27.
[2]. Ogasawara S, et al. Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation. Bioorg Med Chem. 2015;23(19):6246-6249.
[3]. Treis D, et al. Targeted inhibition of WIP1 and histone H3K27 demethylase activity synergistically suppresses neuroblastoma growth. Cell Death Dis. 2025;16(1):318. Published 2025 Apr 19.