LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson’s Disease, Where Do We Stand?
Identifieur interne : 000066 ( Pmc/Checkpoint ); précédent : 000065; suivant : 000067LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson’s Disease, Where Do We Stand?
Auteurs : Jean-Marc Taymans [France] ; Elisa Greggio [Italie]Source :
- Current Neuropharmacology [ 1570-159X ] ; 2016.
Abstract
One of the most promising therapeutic targets for potential diseasemodifying treatment of Parkinson’s disease (PD) is leucine-rich repeat kinase 2 (LRRK2). Specifically, targeting LRRK2’s kinase function has generated a lot of interest from both industry and academia. This work has yielded several published studies showing the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The availability of these experimental drugs is contributing to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition in preclinical models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to expand efficacy studies in preclinical models of progressive PD. Future work in the LRRK2 inhibition field must therefore be directed towards developing molecules and treatment regimens which demonstrate efficacy in mammalian models of disease in conditions where safety liabilities are reduced to a minimum.
Url:
DOI: 10.2174/1570159X13666151030102847
PubMed: 26517051
PubMed Central: 4857626
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>One of the most promising therapeutic targets for potential diseasemodifying
treatment of Parkinson’s disease (PD) is leucine-rich repeat kinase 2 (LRRK2).
Specifically, targeting LRRK2’s kinase function has generated a lot of interest from
both industry and academia. This work has yielded several published studies showing
the feasibility of developing potent, selective and brain permeable LRRK2 kinase
inhibitors. The availability of these experimental drugs is contributing to filling in the
gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition
in preclinical models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while
strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to
expand efficacy studies in preclinical models of progressive PD. Future work in the LRRK2 inhibition field must
therefore be directed towards developing molecules and treatment regimens which demonstrate efficacy in mammalian
models of disease in conditions where safety liabilities are reduced to a minimum.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Curr Neuropharmacol</journal-id>
<journal-id journal-id-type="iso-abbrev">Curr Neuropharmacol</journal-id>
<journal-id journal-id-type="publisher-id">CN</journal-id>
<journal-title-group><journal-title>Current Neuropharmacology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1570-159X</issn>
<issn pub-type="epub">1875-6190</issn>
<publisher><publisher-name>Bentham Science Publishers</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26517051</article-id>
<article-id pub-id-type="pmc">4857626</article-id>
<article-id pub-id-type="publisher-id">CN-14-214</article-id>
<article-id pub-id-type="doi">10.2174/1570159X13666151030102847</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson’s Disease, Where Do We Stand?</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Taymans</surname>
<given-names>Jean-Marc</given-names>
</name>
<xref ref-type="aff" rid="aff1">a</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Greggio</surname>
<given-names>Elisa</given-names>
</name>
<xref ref-type="aff" rid="aff2">b</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>a</label>
Université de Lille, Inserm, CHU Lille, UMR-S1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France;</aff>
<aff id="aff2"><label>b</label>
Department of Biology, University of Padova, 35131, Padova, Italy</aff>
<author-notes><corresp id="cor1"><label>*</label>
Address correspondence to this author at the Jean-Pierre Aubert Research
Center, UMR-S1172,rue Polonovski - 1 place de Verdun, 59045 Lille, France;
Tel: +33320169222; E-mail: <email xlink:href="jean-marc.taymans@inserm.fr">jean-marc.taymans@inserm.fr</email>
and Department
of Biology, University of Padova, 35131, Padova, Italy;
E-mail: <email xlink:href="elisa.greggio@unipd.it">elisa.greggio@unipd.it</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>4</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><month>4</month>
<year>2016</year>
</pub-date>
<volume>14</volume>
<issue>3</issue>
<fpage>214</fpage>
<lpage>225</lpage>
<history><date date-type="received"><day>21</day>
<month>4</month>
<year>2015</year>
</date>
<date date-type="rev-recd"><day>17</day>
<month>6</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>17</day>
<month>6</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© 2016 Bentham Science Publishers </copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Jean-Marc and Greggio</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (<uri xlink:type="simple" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</uri>
) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.</license-p>
</license>
</permissions>
<abstract><p>One of the most promising therapeutic targets for potential diseasemodifying
treatment of Parkinson’s disease (PD) is leucine-rich repeat kinase 2 (LRRK2).
Specifically, targeting LRRK2’s kinase function has generated a lot of interest from
both industry and academia. This work has yielded several published studies showing
the feasibility of developing potent, selective and brain permeable LRRK2 kinase
inhibitors. The availability of these experimental drugs is contributing to filling in the
gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition
in preclinical models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while
strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to
expand efficacy studies in preclinical models of progressive PD. Future work in the LRRK2 inhibition field must
therefore be directed towards developing molecules and treatment regimens which demonstrate efficacy in mammalian
models of disease in conditions where safety liabilities are reduced to a minimum.</p>
</abstract>
<kwd-group><title>Keywords</title>
<kwd>kinase inhibitor</kwd>
<kwd>LRRK2</kwd>
<kwd>Parkinson’s disease</kwd>
<kwd>phenotypic assay.</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="F1" position="float"><label>Fig. (1)</label>
<caption><p>A) Schematic of LRRK2 domain structure and phosphorylation sites. Sites above the schematic include cellular transphosphorylation
sites (at ANK-LRR interdomain region) and autophosphorylation sites (light grey). Please note that phosphosites shown are confirmed in at
least 2 independent studies, additional reported phosphosites can be found in references [27, 32, 36, 65, 115, 116]. Below the schematic,
disease mutants are indicated in black, substitutions in italics are risk factor mutations. Arrows (for S910/S935/S955/S973/S1292) indicate the
most common regulation of phosphorylation (up or down) observed across most disease mutants. ARM, armadillo domain; ANK, ankyrin
repeat domain; LRR, leucine rich repeat domain; ROC, Ras of Complex proteins domain; COR, C-terminal of ROC domain; Kin, kinase
domain; WD40, WD40 domain. B) Schematic of the LRRK2 signaling cascade. The structure of the LRRK2 dimer is depicted with its 7
domains (including ROC-GTPase and Kinase domains), with its phosphorylation (black P on light background) and autophosphorylation sites
(white P on dark background). Kinase activity is represented by both autophosphorylation and phosphorylation of substrate. C) Schematic of
strategies for LRRK2 targeting, including targeting kinase and GTPase functions, targeting phosphoreguylators of LRRK2 such as
phosphatases, or targeting LRRK2 dimerization or interaction with cellular partners. Thus far, compounds have been reported targeting
LRRK2 kinase and GTPase functions (see text for more details).</p>
</caption>
<graphic xlink:href="CN-14-214_F1"></graphic>
</fig>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Overview of key LRRK2 kinase inhibitors.</p>
</caption>
<table frame="border" rules="all" width="100%"><thead><tr><th align="center" rowspan="1" colspan="1">Compound ID</th>
<th align="center" rowspan="1" colspan="1"><italic>In Vitro</italic>
Activity <break></break>
(IC50 WT, nM)</th>
<th align="center" rowspan="1" colspan="1">Cellular Activity S935 (IC50 WT, nM)</th>
<th align="center" rowspan="1" colspan="1">Brain Penetrance</th>
<th align="center" rowspan="1" colspan="1">Off Target Kinases/<break></break>
Total Tested</th>
<th align="center" rowspan="1" colspan="1">Refs.</th>
</tr>
</thead>
<tbody><tr><td valign="middle" align="center" rowspan="1" colspan="1">LRRK2-IN1</td>
<td valign="middle" align="center" rowspan="1" colspan="1">13</td>
<td valign="middle" align="center" rowspan="1" colspan="1">280</td>
<td valign="middle" align="center" rowspan="1" colspan="1">No</td>
<td valign="middle" align="center" rowspan="1" colspan="1">12/442</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R77" ref-type="bibr">77</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">CZC25146</td>
<td valign="middle" align="center" rowspan="1" colspan="1">5</td>
<td valign="middle" align="center" rowspan="1" colspan="1">44</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Low</td>
<td valign="middle" align="center" rowspan="1" colspan="1">5/185</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R106" ref-type="bibr">106</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">HG-10-102-01</td>
<td valign="middle" align="center" rowspan="1" colspan="1">20</td>
<td valign="middle" align="center" rowspan="1" colspan="1">650</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">2/451</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R107" ref-type="bibr">107</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">GSK2578215A</td>
<td valign="middle" align="center" rowspan="1" colspan="1">11</td>
<td valign="middle" align="center" rowspan="1" colspan="1">992</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Low</td>
<td valign="middle" align="center" rowspan="1" colspan="1">2/451</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R108" ref-type="bibr">108</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">GNE7915</td>
<td valign="middle" align="center" rowspan="1" colspan="1">37</td>
<td valign="middle" align="center" rowspan="1" colspan="1">194</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">2/451</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R109" ref-type="bibr">109</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">GNE-0877</td>
<td valign="middle" align="center" rowspan="1" colspan="1">1</td>
<td valign="middle" align="center" rowspan="1" colspan="1">3</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">4/190</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R110" ref-type="bibr">110</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">GNE-9605</td>
<td valign="middle" align="center" rowspan="1" colspan="1">2</td>
<td valign="middle" align="center" rowspan="1" colspan="1">19</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">-</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R110" ref-type="bibr">110</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">Indolinone 5<break></break>
(= Nov-LRRK2-11)</td>
<td valign="middle" align="center" rowspan="1" colspan="1">9</td>
<td valign="middle" align="center" rowspan="1" colspan="1">-</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">-</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R111" ref-type="bibr">111</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">Indolinone 15b</td>
<td valign="middle" align="center" rowspan="1" colspan="1">15</td>
<td valign="middle" align="center" rowspan="1" colspan="1">-</td>
<td valign="middle" align="center" rowspan="1" colspan="1">-</td>
<td valign="middle" align="center" rowspan="1" colspan="1">0/46</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R112" ref-type="bibr">112</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">PF-06447475</td>
<td valign="middle" align="center" rowspan="1" colspan="1">3</td>
<td valign="middle" align="center" rowspan="1" colspan="1">25</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">3/39</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R113" ref-type="bibr">113</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">JH-II-127</td>
<td valign="middle" align="center" rowspan="1" colspan="1">6,6</td>
<td valign="middle" align="center" rowspan="1" colspan="1">100-300</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Yes</td>
<td valign="middle" align="center" rowspan="1" colspan="1">-</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R114" ref-type="bibr">114</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T2" position="float"><label>Table 2</label>
<caption><p>Overview of studies of potential safety liability of LRRK2 kinase inhibitors in mammalian animal models.</p>
</caption>
<table frame="border" rules="all" width="100%"><thead><tr><th align="center" rowspan="1" colspan="1">Compound</th>
<th align="center" rowspan="1" colspan="1">Dose</th>
<th align="center" rowspan="1" colspan="1">Species</th>
<th align="center" rowspan="1" colspan="1">Potential Safety Liability</th>
<th align="center" rowspan="1" colspan="1">Refs.</th>
</tr>
</thead>
<tbody><tr><td valign="middle" align="center" rowspan="1" colspan="1">GNE-7915</td>
<td valign="middle" align="center" rowspan="1" colspan="1">200 – 300 mg/kg p.o. twice daily for 15 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Mouse</td>
<td valign="middle" align="center" rowspan="1" colspan="1">No microscopic effects observed in lungs or kidneys</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R23" ref-type="bibr">23</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1"> </td>
<td valign="middle" align="center" rowspan="1" colspan="1">10, 50 or 100 mg/kg p.o. daily for 7 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Rat</td>
<td valign="middle" align="center" rowspan="1" colspan="1">No microscopic effects observed in lungs or kidneys</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R23" ref-type="bibr">23</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1"> </td>
<td valign="middle" align="center" rowspan="1" colspan="1">10, 25 or 65 mg/kg p.o. daily for 7 days or 30 mg/kg for 29 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Cynomolgus monkey</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Increased vacuolation of type II lung cells</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R23" ref-type="bibr">23</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">GNE-0877</td>
<td valign="middle" align="center" rowspan="1" colspan="1">30 – 65 mg/kg p.o. twice daily for 15 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Mouse</td>
<td valign="middle" align="center" rowspan="1" colspan="1">No microscopic effects observed in lungs or kidneys</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R23" ref-type="bibr">23</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1"> </td>
<td valign="middle" align="center" rowspan="1" colspan="1">30, 75 or 200 mg/kg p.o. once daily for 7 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Rat</td>
<td valign="middle" align="center" rowspan="1" colspan="1">No microscopic effects observed in lungs or kidneys</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R23" ref-type="bibr">23</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1"> </td>
<td valign="middle" align="center" rowspan="1" colspan="1">6 or 20 mg/kg p.o. daily for 29 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Cynomolgus monkey</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Increased vacuolation of type II lung cells</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R23" ref-type="bibr">23</xref>
]</td>
</tr>
<tr><td valign="middle" align="center" rowspan="1" colspan="1">Indolinone 5 <break></break>
(= Nov-LRRK2-11)</td>
<td valign="middle" align="center" rowspan="1" colspan="1">30 mg/kg p.o. twice daily for 5 days</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Mouse</td>
<td valign="middle" align="center" rowspan="1" colspan="1">Loss of LRRK2 expression, cellular effects not tested</td>
<td valign="middle" align="center" rowspan="1" colspan="1">[<xref rid="R25" ref-type="bibr">25</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>France</li>
<li>Italie</li>
</country>
<region><li>Hauts-de-France</li>
<li>Nord-Pas-de-Calais</li>
</region>
<settlement><li>Lille</li>
</settlement>
</list>
<tree><country name="France"><region name="Hauts-de-France"><name sortKey="Taymans, Jean Marc" sort="Taymans, Jean Marc" uniqKey="Taymans J" first="Jean-Marc" last="Taymans">Jean-Marc Taymans</name>
</region>
</country>
<country name="Italie"><noRegion><name sortKey="Greggio, Elisa" sort="Greggio, Elisa" uniqKey="Greggio E" first="Elisa" last="Greggio">Elisa Greggio</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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