Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
J Med Chem. 2023 Dec 14;66(23):16075-16090. doi: 10.1021/acs.jmedchem.3c01491. Epub 2023 Nov 16.
Recent studies have shown that the epigenetic protein histone deacetylase 11 (HDAC11) is highly expressed in the brain and critically modulates neuroimmune functions, making it a potential therapeutic target for neurological disorders. Herein, we report the development of PB94, which is a novel HDAC11 inhibitor. PB94 exhibited potency and selectivity against HDAC11 with IC = 108 nM and >40-fold selectivity over other HDAC isoforms. Pharmacokinetic/pharmacodynamic evaluation indicated that PB94 possesses promising drug-like properties. Additionally, PB94 was radiolabeled with carbon-11 as [C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for drug development in live animals. Furthermore, we demonstrated that neuropathic pain was associated with brain upregulation of HDAC11 and that pharmacological inhibition of HDAC11 by PB94 ameliorated neuropathic pain in a mouse model. Collectively, our findings support further development of PB94 as a selective HDAC11 inhibitor for neurological indications, including pain.
最近的研究表明，表观遗传蛋白组蛋白去乙酰化酶 11（HDAC11）在大脑中高度表达，并对神经免疫功能有重要的调节作用，使其成为治疗神经紊乱的潜在治疗靶点。在此，我们报告了新型 HDAC11 抑制剂 PB94 的研发。PB94 对 HDAC11 具有效力和选择性，IC50 值为 108 nM，对其他 HDAC 同工酶的选择性超过 40 倍。药代动力学/药效学评价表明 PB94 具有良好的药物特性。此外，用碳-11 对 PB94 进行放射性标记，制成 [C]PB94，用于正电子发射断层扫描（PET），结果显示其具有显著的脑摄取和代谢特性，适合在活体动物中进行药物开发。此外，我们证明神经性疼痛与大脑中 HDAC11 的上调有关，而 PB94 抑制 HDAC11 可改善小鼠模型中的神经性疼痛。综上所述，我们的研究结果支持进一步开发 PB94 作为治疗神经疾病的选择性 HDAC11 抑制剂，包括疼痛。
