结合 Spop 的双功能降解剂：肿瘤免疫治疗的新方法

This study aims to design and synthesize bifunctional small molecules as PD-L1 degraders by leveraging the unexplored E3 ligase SPOP, aiming to overcome the limitations of existing degraders and evaluate their potential in cancer immunotherapy.

A series of SPOP-based bifunctional small molecules were designed and synthesized. Their PD-L1 inhibitory and degradation activities were assessed using HTRF and western blot assays, respectively. Mechanistic studies (His pull-down, bio-layer interferometry, western blot) were performed to verify ternary complex formation with PD-L1 and SPOP. In vivo pharmacokinetic properties and antitumor efficacy were evaluated in a B16-F10 tumor model, with analysis of tumor-infiltrating lymphocytes (TILs) to explore immune microenvironment effects.

Compound SPOP9 exhibited potent PD-L1 inhibition (IC 50 = 357.2 nM) and degradation (DC 50 = 1.0 M). Mechanistic studies confirmed its assembly into a stable ternary complex with PD-L1 and SPOP. SPOP9 showed favorable in vivo bioavailability (F = 74.8 %) and, at 10 mg/kg (i.p.), reduced tumor weight by 44 % in B16-F10 mice, superior to anti-PD-L1 antibody (TGI = 34.4 %). TIL analysis indicated SPOP9 activated the tumor immune microenvironment and downregulated PD-L1.

SPOP9, as the first SPOP-binding bifunctional PD-L1 degrader, demonstrates promising preclinical efficacy and pharmacokinetic properties, addressing key limitations of existing degraders. It merits further investigation as a potential agent for cancer immunotherapy.