Allosteric inhibition of LRRK2, where are we now

Ahmed Soliman, Fatma Nihan Cankara, Arjan Kortholt*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

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Parkinson's disease (PD) is the second most common neurodegenerative disease. In recent years, it has been shown that leucine-rich repeat kinase 2 (LRRK2) has a crucial function in both familial and sporadic forms of PD. LRRK2 pathogenic mutations are thought to result in an increase in LRRK2 kinase activity. Thus, inhibiting LRRK2 kinase activity has become a main therapeutic target. Many compounds capable of inhibiting LRRK2 kinase activity with high selectivity and brain availability have been described. However, the safety of long-term use of these ATP-competitive LRRK2 kinase inhibitors has been challenged by several studies. Therefore, alternative ways of targeting LRRK2 activity will have a great benefit. In this review, we discuss the recent progress in the development of allosteric inhibitors of LRRK2, mainly via interfering with GTPase activity, and propose potential new intra and interprotein interactions targets that can lead to open doors toward new therapeutics.

Original languageEnglish
Article numberBST20200424
Pages (from-to)2185-2194
Number of pages10
JournalBiochemical Society Transactions
Issue number5
Early online date20-Oct-2020
Publication statusPublished - 30-Oct-2020


  • GTPase
  • Parkinson's disease
  • dimerization
  • kinase inhibitors
  • leucine rich repeat kinase

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