Yayınlanmış 1 Ocak 2020 | Sürüm v1
Dergi makalesi Açık

The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

  • 1. Univ Groningen, Dept Pharm, Grp Drug Design, A Deusinglaan 1, NL-9713 AV Groningen, Netherlands
  • 2. Univ Groningen, Dept Mol Pharmacol, Groningen Res Inst Pharm GRIP, A Deusinglaan 1, NL-9713 AV Groningen, Netherlands
  • 3. Univ Groningen, Dept Cell Biochem, Groningen Inst Biomol Sci & Biotechnol, Nijenborgh 7, NL-9747 AG Groningen, Netherlands

Açıklama

Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.

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