Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
Drug Metabolism and Pharmacokinetics Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
Sci Rep. 2021 Jul 29;11(1):15423. doi: 10.1038/s41598-021-94923-w.
Accumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Those diseases are collectively termed tauopathies. Tau pathology is associated with axonal degeneration because tau binds to microtubules (MTs), a component of axon and regulates their stability. The acetylation state of MTs contributes to stability and histone deacetylase 6 (HDAC6) is a major regulator of MT acetylation status, suggesting that pharmacological HDAC6 inhibition could improve axonal function and may slow the progression of tauopathy. Here we characterize N-[(1R,2R)-2-{3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}cyclohexyl]-2,2,3,3,3-pentafluoropropanamide (T-518), a novel, potent, highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics. T-518 shows potent inhibitory activity against HDAC6 and superior selectivity over other HDACs compared with the known HDAC6 inhibitors in the enzyme and cellular assays. T-518 showed brain penetration in an oral dose and blocked HDAC6-dependent tubulin deacetylation at Lys40 in mouse hippocampus. A 2-week treatment restored impaired axonal transport and novel object recognition in the P301S tau Tg mouse, tauopathy model, while a 3-month treatment also decreased RIPA-insoluble tau accumulation. Pharmaceutical inhibition of HDAC6 is a potential therapeutic strategy for tauopathy, and T-518 is a particularly promising drug candidate.
tau 蛋白的积累是与年龄相关的神经退行性疾病（如阿尔茨海默病和进行性核上性麻痹）的关键病理学。这些疾病统称为 tau 病。tau 病理学与轴突变性有关，因为 tau 与微管（MTs）结合，MTs 是轴突的组成部分，调节其稳定性。MTs 的乙酰化状态有助于稳定性，组蛋白去乙酰化酶 6（HDAC6）是 MT 乙酰化状态的主要调节剂，这表明药理学抑制 HDAC6 可以改善轴突功能，并可能减缓 tau 病的进展。在这里，我们描述了 N-[(1R,2R)-2-{3-[5-(二氟甲基)-1,3,4-恶二唑-2-基]-5-氧代-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基}环己基]-2,2,3,3,3-五氟丙酰胺（T-518），这是一种新型、有效、高度选择性的 HDAC6 抑制剂，具有临床有利的药效动力学。T-518 在酶和细胞测定中对 HDAC6 具有很强的抑制活性，与已知的 HDAC6 抑制剂相比，对其他 HDACs 具有优越的选择性。T-518 在口服剂量下显示出脑穿透性，并在小鼠海马体中阻断了 HDAC6 依赖性微管蛋白 Lys40 的去乙酰化。2 周的治疗恢复了 P301S tau Tg 小鼠（tau 病模型）受损的轴突运输和新物体识别，而 3 个月的治疗也减少了 RIPA 不溶性 tau 的积累。HDAC6 的药物抑制是 tau 病的一种潜在治疗策略，而 T-518 是一种特别有前途的候选药物。
