Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K.
Charles River, Darwinweg 24, Leiden 2333 CR, The Netherlands.
J Med Chem. 2022 Sep 22;65(18):12445-12459. doi: 10.1021/acs.jmedchem.2c01149. Epub 2022 Sep 13.
Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin () gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan. To further investigate the role of HDAC4 in cellular models of HD, we have developed bifunctional degraders of the protein and report the first potent and selective degraders of HDAC4 that show an effect in multiple cell lines, including HD mouse model-derived cortical neurons. These degraders act via the ubiquitin-proteasomal pathway and selectively degrade HDAC4 over other class IIa HDAC isoforms (HDAC5, HDAC7, and HDAC9).
亨廷顿病（HD）是一种致命的常染色体显性神经退行性疾病，由亨廷顿（）基因中的 CAG 重复扩展引起。该基因翻译的产物是一种高度聚集倾向的蛋白质，含有 >35 个重复的聚谷氨酰胺片段（mHTT），已被证明与 HD 小鼠模型中的细胞质包涵体中的组蛋白去乙酰化酶 4（HDAC4）共定位。在 HD 小鼠模型中降低 HDAC4 的遗传表达导致 mHTT 的聚集延迟，同时改善神经表型和延长寿命。为了进一步研究 HDAC4 在 HD 的细胞模型中的作用，我们开发了该蛋白的双功能降解剂，并报告了第一个有效的和选择性的 HDAC4 降解剂，其在多个细胞系中显示出效果，包括源自 HD 小鼠模型的皮质神经元。这些降解剂通过泛素-蛋白酶体途径发挥作用，选择性地降解 HDAC4 而不是其他 IIa 类 HDAC 同工酶（HDAC5、HDAC7 和 HDAC9）。
