GSK2830371 | WIP1 phosphatase inhibitor

GSK2830371 is (1404456-53-6) a potent allosteric inhibitor of WIP1 phosphatase (IC₅₀ = 6 nM), a negative regulator of the DNA damage response.¹ It displayed no inhibition of 21 other phosphatases. Active in xenograft model DoHH2 B-cell lymphoma.  GSK2830371 in combination with MDM2 inhibitors has been shown to be efficacious in the treatment of various cancers including liver adenocarcinoma², acute myeloid leukemia³, and breast⁴. It enhances phosphorylation of the tumor suppressor p53 leading to activation.^5,6

References/Citations:

1. Gilmartin et al. (2014), Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction; Nat. Chem. Biol., 10 181
2. Wu et al. (2022), In vitro and in vivo study of GSK2830317 and RG7388 combination in liver adenocarcinoma; Am. J. Cancer Res., 12 4399
3. Fontana et al. (2021), Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a; Biomedicines, 9 388
4. Pechackova et al. (2016), Inhibition of WIP1 phosphatase sensitizes breast cancer cells to genotoxic stress and to MDM2 antagonist nutlin-3; Oncotarget, 7 14458
5. Esfandiari et al. (2016), Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner; Mol. Cancer Ther., 15 379
6. Wu et al. (2021), WIP1 Inhibition by GSK2830371 Potentiates HDM201 through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells; Cancers (Basel), 13 3876