The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease

Xu, Tao; Xing, Shuaishuai; Ma, Mingkang; Xu, Ziwei; Guan, Qinghua; Chen, Yuting; Feng, Feng; Liu, Wenyuan; Chen, Tingkai; Yao, Chen; Sun, Haopeng

doi:10.1021/acs.jmedchem.2c01552

Cited by 11 publications

(9 citation statements)

References 173 publications

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“…Developing selective inhibitors of LRRK2 has been a major focus in treating LRRK2-associated PD. Various targeting strategies are currently being explored, including ATP-competitive type I and type II inhibitors, LRRK2 dimerization inhibitors, LRRK2 G2019S selective inhibitors, antisense oligonucleotide, proteolysis targeting chimeras (PROTACs), and LRRK2-targeting nanobodies [13][14][15][16][17][18][19][20] . Currently, LRRK2-specific type I kinase inhibitors are available, and type II inhibitors are under active exploration.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Zhu,

Hixson,

et al. 2024

Cell Discov

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LRRK2 is one of the most promising drug targets for Parkinson’s disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2–inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2–inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.

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Section: Introductionmentioning

confidence: 99%

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Zhu,

Hixson,

et al. 2024

Cell Discov

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“…The most frequent PD-linked mutations in LRRK2 increase its kinase activity (5)(6)(7)(8), but hyperactivation of an otherwise wild-type (WT) LRRK2 has also been reported in idiopathic PD (9). As a result, LRRK2 has become a major target for the development of kinase inhibitors as therapeutics for PD (10,11).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Parkinson’s disease–related LRRK2 by type I and type II kinase inhibitors: Activity and structures

Sanz Murillo,

Villagran Suarez,

Dederer

et al. 2023

Sci. Adv.

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson’s disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo–electron microscopy structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type I inhibitor MLi-2 and the broad-spectrum type II inhibitor GZD-824. Our structures revealed an active-like LRRK2 kinase in the type I inhibitor complex, and an inactive DYG-out in the type II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structures provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.

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“…Interestingly, CBE induces, in HEK-293 cells ( Figure 10 A), a similar cellular phenotype as HEK-293 LRRK2 KO cells exposed to ROT ( Figure 10 B). These observations imply that the combined development of LRRK2 inhibitors [ 98 , 99 ] and compounds for recovering GCase activity [ 38 , 100 ] might be promising therapeutic agents for PD.…”

Section: Discussionmentioning

confidence: 99%

Rotenone Blocks the Glucocerebrosidase Enzyme and Induces the Accumulation of Lysosomes and Autophagolysosomes Independently of LRRK2 Kinase in HEK-293 Cells

Perez-Abshana,

Mendivil-Perez,

Velez-Pardo

et al. 2023

IJMS

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Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra and the intraneuronal presence of Lewy bodies (LBs), composed of aggregates of phosphorylated alpha-synuclein at residue Ser129 (p-Ser129α-Syn). Unfortunately, no curative treatment is available yet. To aggravate matters further, the etiopathogenesis of the disorder is still unresolved. However, the neurotoxin rotenone (ROT) has been implicated in PD. Therefore, it has been widely used to understand the molecular mechanism of neuronal cell death. In the present investigation, we show that ROT induces two convergent pathways in HEK-293 cells. First, ROT generates H2O2, which, in turn, either oxidizes the stress sensor protein DJ-Cys106-SH into DJ-1Cys106SO3 or induces the phosphorylation of the protein LRRK2 kinase at residue Ser395 (p-Ser395 LRRK2). Once active, the kinase phosphorylates α-Syn (at Ser129), induces the loss of mitochondrial membrane potential (ΔΨm), and triggers the production of cleaved caspase 3 (CC3), resulting in signs of apoptotic cell death. ROT also reduces glucocerebrosidase (GCase) activity concomitant with the accumulation of lysosomes and autophagolysosomes reflected by the increase in LC3-II (microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate II) markers in HEK-293 cells. Second, the exposure of HEK-293 LRRK2 knockout (KO) cells to ROT displays an almost-normal phenotype. Indeed, KO cells showed neither H2O2, DJ-1Cys106SO3, p-Ser395 LRRK2, p-Ser129α-Syn, nor CC3 but displayed high ΔΨm, reduced GCase activity, and the accumulation of lysosomes and autophagolysosomes. Similar observations are obtained when HEK-293 LRRK2 wild-type (WT) cells are exposed to the inhibitor GCase conduritol-β-epoxide (CBE). Taken together, these observations imply that the combined development of LRRK2 inhibitors and compounds for recovering GCase activity might be promising therapeutic agents for PD.

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The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease

Cited by 11 publications

References 173 publications

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Inhibition of Parkinson’s disease–related LRRK2 by type I and type II kinase inhibitors: Activity and structures

Rotenone Blocks the Glucocerebrosidase Enzyme and Induces the Accumulation of Lysosomes and Autophagolysosomes Independently of LRRK2 Kinase in HEK-293 Cells

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