ESCAPE Bio, South San Francisco, California 94080, United States.
Aptuit, an Evotec Company, Verona 37135, Italy.
J Med Chem. 2020 Dec 10;63(23):14821-14839. doi: 10.1021/acs.jmedchem.0c01243. Epub 2020 Nov 16.
Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.
在亮氨酸丰富重复激酶 2（LRRK2）基因中发现的致病性变异可导致帕金森病以显性遗传的方式发生。这些致病性变异，其中 G2019S 是最常见的，导致异常高的激酶活性，并且正在研究抑制这种活性的化合物作为潜在的疾病修饰治疗方法。由于 LRRK2 调节重要的细胞过程，因此开发能够选择性地靶向致病性变异体而不影响正常 LRRK2 活性的抑制剂可能在杂合子携带者中具有潜在优势。我们进行了高通量筛选，并鉴定出一种优先抑制 G2019S-LRRK2 的单一选择性化合物。对该支架的优化导致了一系列新型、有效且高度选择性的 G2019S-LRRK2 抑制剂。
