GSK2830371

**GSK2830371** is a potent, selective, orally active allosteric small molecule inhibitor of PPM1D (also known as WIP1), a serine/threonine phosphatase involved in DNA damage response and p53 regulation. Developed initially by **GSK** (GlaxoSmithKline) and later associated with **AstraZeneca**, it binds with high affinity (IC50 ~6 nM) to a unique hinge region (residues 155-166) near the flap subdomain outside the catalytic domain, locking PPM1D in an inactive conformation by shifting its equilibrium from active to inactive states, as shown by HDX-MS and SV-AUC. This non-competitive inhibition enhances phosphorylation of PPM1D substrates like p53 (Ser15), Chk2 (Thr68), H2AX (Ser139), and ATM (Ser1981), stabilizing p53, upregulating p21/WAF1, and inducing apoptosis selectively in p53 wild-type cancer cells; it also promotes ubiquitination-dependent degradation of PPM1D protein. Preclinical studies demonstrate anti-tumor activity in neuroblastoma, cholangiocarcinoma, and other cancers, often potentiating MDM2 inhibitors, chemotherapeutics (e.g., doxorubicin, etoposide), or HDM201, with in vivo efficacy in orthotopic neuroblastoma xenografts at 25 mg/kg IP without overt toxicity.