PP5 degrader DDO-4279 outperforms semaglutide in reducing body weight and hepatic steatosis in ob/ob mice

Protein phosphatase 5 (PP5), a crucial member of the serine/threonine phosphatase family, is increasingly recognized for its involvement in various pathologies, including obesity and certain tumors. Despite its therapeutic potential, developing highly specific and potent PP5 modulators has been challenging. This difficulty stems from the high sequence homology and strong electronegativity characteristic of its catalytic domain, making selective targeting difficult for traditional inhibitors. Current obesity treatments often target incretin pathways, but novel mechanisms are sought to address diverse patient needs and improve efficacy or reduce side effects.

Researchers identified DDO-4279, a novel PP5 degrader, from an existing PP5 inhibitor library. The study investigated its mechanism of action and therapeutic efficacy in an in vivo model of obesity. They administered DDO-4279 dose-dependently to ob/ob mice, a common genetic model for obesity and metabolic dysfunction. The primary endpoints included changes in body weight gain, assessment of hepatomegaly, and evaluation of hepatic steatosis. For comparison, the clinical anti-obesity drug semaglutide was used as an active control arm. The study also assessed potential renal toxicity to evaluate the compound's safety profile.

DDO-4279 demonstrated a unique mechanism, selectively degrading PP5 via the ubiquitin-proteasome pathway, a distinct approach from conventional PP5 inhibitors. This degradation led to the downregulation of key PP5 substrate proteins, specifically PPARγ and GR. Endowed with favorable pharmacokinetic profiles, DDO-4279 exhibited significant therapeutic effects in ob/ob mice. The compound dose-dependently reduced body weight gain, notably outperforming the clinical drug semaglutide in this regard. Furthermore, DDO-4279 effectively ameliorated hepatomegaly and hepatic steatosis, indicating a positive impact on liver health. Importantly, the study reported no renal toxicity associated with DDO-4279 administration. This suggests a potentially favorable safety profile for this novel therapeutic agent.

DDO-4279 dose-dependently reduced body weight gain in ob/ob mice, outperforming the clinical drug semaglutide, and ameliorated hepatomegaly and hepatic steatosis.