Discovery of Selective LRRK2 Inhibitors Guided by Computational Analysis and Molecular Modeling

Chen, Huifen; Chan, Bryan; Drummond, Jason; Estrada, Anthony A.; Gunzner-Toste, Janet; Liu, Xingrong; Liu, Yichin; Moffat, John G.; Shore, Daniel G.; Sweeney, Zachary K.; Tran, Thuy; Wang, Shumei; Zhao, Gui‐Ling; Zhu, Haitao; Burdick, Daniel J.

doi:10.1021/jm300452p

Cited by 78 publications

(94 citation statements)

References 62 publications

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“…The inhibitors were also assayed for inhibition of Janus kinase 2 (JAK2), as previous efforts had confirmed that JAK2/LRRK2 biochemical selectivity correlated with biochemical selectivity against the broader kinome. 22,23 The 3-and 5-amino-linked pyrazoles (2 and 3) demonstrated good JAK2/LRRK2 selectivity but appeared to have inferior potency for LRRK2 in our biochemical screen and cell-based LRRK2 autophosphorlyation assay when compared to the 4-linked aminopyrazoles (5−7). The poor JAK2 selectivity of compound 4 (2.7×) confirmed that a nitrogen lone pair (e.g., compound 2) or 3-/5-substituent was required to achieve good selectivity.…”

Section: P Arkinson's Disease (Pd) Is a Neurodegenerative Disordermentioning

confidence: 93%

“…Additionally, our lead optimization efforts toward 1 established the importance of occupying the vector adjacent to the hingebinding anilino N-H motif (methoxy group in 1) for overall kinase selectivity. 22,23 The incorporation of this "selectivity handle" was one of the major considerations in the design of possible aniline replacements. Lastly, the morpholine carboxamide moiety occupies a solvent-exposed region of the active site.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor

Chan¹,

Estrada²,

Chen³

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilinoaminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs. KEYWORDS: LRRK2, kinase inhibitor, Parkinson's disease, CYP1A2 inhibition P arkinson's disease (PD) is a neurodegenerative disorder that affects approximately 1% of the world's population over the age of 65. 1 Identification of a disease-modifying or neuroprotective therapeutic for PD patients remains a significant challenge. Recently, genetic research has revealed a connection between a missense mutation (G2019S) in the leucine-rich repeat kinase 2 (LRRK2) gene and a number of familial and idiopathic PD cases. 2−9 Significantly, multiple reports have shown that this mutation enhances the kinase activity of LRRK2. 10−17 The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has therefore been proposed as a potential treatment for PD. 18−23 We recently reported the first disclosure of a series of highly potent, selective, and brain-penetrable anilino-pyrimidine LRRK2 inhibitors as exemplified by compound 1. 22,23 Examination of the liabilities of 1 and structurally similar analogues revealed (a) moderate to poor aqueous solubility (thermodynamic solubility of 1 at pH 7.4 < 0.9 μg/mL), (b) potential for ortho-quinoneimine reactive metabolite formation, and (c) a morpholinocarboxamide motif as a major site of metabolism as indicated by metabolite identification studies (MetID). In an effort to improve upon 1 and mitigate potential safety risks, we initiated a campaign to identify a suitable bioisosteric replacement for the aniline functionality. This approach resulted in the discovery of a novel series of highly selective aminopyrazole LRRK2 inhibitors.Docking experiments using a JAK-2-derived homology model of LRRK2 suggested that compound 1 binds in the ATP binding site of LRRK2 as shown in Figure 1. 22,23 In designing anilino-carboxamide replacements, we chose to retain the hinge binding diaminopyrimidine core as well as the C-5 trifluoromethyl group that interacts favorably with the methionine gatekeeper through van der Waal contacts. Additionally, our lead optimization efforts toward 1 established the importance of occupying the vector adjacent to the hingebinding anilino N-H motif (methoxy group in...

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Section: P Arkinson's Disease (Pd) Is a Neurodegenerative Disordermentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor

Chan¹,

Estrada²,

Chen³

et al. 2012

ACS Med. Chem. Lett.

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“…There is no consensus on a "best" template to build LRRK2 kinase domain homology models due to the fact that the kinases for which X-ray crystal structures have been published have at most 30% sequence identity to LRRK2. The most common templates have been from B-Raf [94,101,[129][130][131], JAK-2 [132][133][134][135][136][137][138], MLK1 [132,[136][137][138][139], ROCO4 [131,140], and TAK1 [132,141,142] kinases, chosen based on overall kinase sequence identity, ATP-binding site identity, and/or crossover of inhibitor activity. Consensus from these alignments is that G2019 is the Gly in the conserved DFG motif (DYG in LRRK2) and I2020 is the subsequent residue in the activation loop (Fig.…”

Section: Kinase Domain Pathogenic Mutationsmentioning

confidence: 99%

“…Mutation of A2016 to Thr abolishes activity in some inhibitors [35,140,143], but not others [145][146][147], which is indicative of the inhibitor binding modes. The non-conserved residues L1949, S1954, R1957, and F1883 were identified as potential selectivity handles in the LRRK2 kinase domain, due to their proximity to the ATP-binding pocket for a series of diaminopyrimidine compounds [132][133][134][135]. L1949 near the hinge region was targeted for selectivity since it is a smaller residue than Phe or Tyr, which is found in this position in approximately 60% of the kinome.…”

Section: Using Lrrk2 Structure To Guide Kinase Inhibitor Designmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors

Galatsis

Henderson

Kormos

et al. 2014

Topics in Medicinal Chemistry

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of autosomal dominant Parkinson's disease (PD), accounting for approximately 1% of "sporadic" and 4% of familial cases. These mutations either lead directly to an increased kinase activity (G2019S and I2020T are in the kinase activation loop) or to a reduced GTPase activity (R1441C/G and Y1699C), that in turn positively regulate kinase activity. The physiological substrate of the LRRK2 kinase has yet to be definitively identified, yet autophosphorylation is emerging as a relatively robust measure of its activity. LRRK2 has been implicated in a number of diverse cellular processes such as vesicular trafficking, microtubule dynamics, protein translation control, inflammation, and immune function, all of which have been linked to PD. LRRK2 is a large, multi-domain protein; a thorough understanding of the protein domain organization and identification of interacting partners is important to determine the underlying mechanism of LRRK2. Substantial recent effort has been directed towards identifying potent LRRK2 kinase inhibitors, from the repurposed kinase inhibitors to the first through third generation of LRRK2-focused kinase inhibitors, from a range of chemotypes, which are now providing researchers with new tools to better interrogate LRRK2 function.

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“…16 This residue is a Tyr or Phe in the JAK family ( Figure S3). By directing a methyl (35) or ethyl (36) substituent in this direction, TMLR potency and wtEGFR selectivity were comparable to 13, but markedly increased selectivity against JAK1 was realized, with a modest improvement in JAK2 selectivity for compound 36 (Table 3).…”

mentioning

confidence: 99%