Discovery of DDO-4279 as a PP5 degrader for the treatment of obesity.

PP5, a key member of the serine/threonine phosphatase family, is closely linked to tumors and other diseases such as obesity. However, developing highly specific and potent PP5 modulators remains challenging due to the high homology and strong electronegativity of its catalytic domain. Serendipitously, we identified the PP5 degrader DDO-4279 from our previously established PP5 inhibitor library. Mechanistically, DDO-4279 selectively degrades PP5 via the ubiquitin-proteasome pathway, thereby downregulating PP5 substrate proteins PPARγ and GR, a mechanism entirely distinct from that of conventional PP5 inhibitors. Endowed with favorable pharmacokinetic profiles, DDO-4279 dose-dependently reduced body weight gain in ob/ob mice (outperforming the clinical drug semaglutide), ameliorated hepatomegaly and hepatic steatosis, and exhibited no renal toxicity. Collectively, DDO-4279 emerges as a promising anti-obesity agent with a unique mechanism of action, distinguishing it from traditional PP5 inhibitory strategies.