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开发一种高效和选择性的LRRK2降解剂

John M Hatcher¹, Monika Zwirek², Adil R Sarhan³

¹Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.

Bioorganic & medicinal chemistry letters

|August 17, 2023

概括

研究人员开发了一种新型的PROTAC分子,以准帕金森病 (PD) 中的氨酸丰富的重复激酶2 (LRRK2). 这种分子有效地降低了LRRK2激酶活性和支架功能,为PD提供了潜在的新治疗策略.

科学领域:

神经退行性医学是一种神经退行性药物.
分子生物学分子生物学
药物发现药物发现

背景情况:

帕金森病 (PD) 缺乏疾病修饰疗法.
氨酸丰富的重复激酶2 (LRRK2) 的遗传突变是PD风险因素.
突变的LRRK2表现出增加的激酶活性和神经毒性,其支架功能有助于神经退行.

研究的目的:

开发针对LRRK2.2的酶和支架功能的新疗法.
为LRRK2降解创建向蛋白解的嵌合体 (PROTACs).

主要方法:

开发旨在降解LRRK的PROTAC分子2.2.
对一个特定的PROTAC分子 (JH-XII-03-02) 对468个激酶的面板进行强度和选择性的评估.

主要成果:

该PROTAC分子JH-XII-03-02显示了对LRRK2.2的高强度和选择性.
这种分子有效地消除了LRRK2.2的激酶活性和支架功能.

结论:

针对LRRK2的PROTACs代表了帕金森病的有前途的治疗策略.
JH-XII-03-02对LRRK2激酶和支架功能的双重作用为PD中神经保护提供了一种新的方法.

关键词:

这是LRRK2 这是一种LRRK2降解剂.在MLi-2中使用.这就是PROTAC.

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