Literature DB >> 23066449

Brain Penetrant LRRK2 Inhibitor.

Hwan Geun Choi1, Jinwei Zhang, Xianming Deng, John M Hatcher, Matthew P Patricelli, Zheng Zhao, Dario R Alessi, Nathanael S Gray.   

Abstract

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report a 2-anilino-4-methylamino-5-chloropyrimidine, HG-10-102-01(4) is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 µM in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.

Entities:  

Year:  2012        PMID： 23066449      PMCID： PMC3467149          DOI： 10.1021/ml300123a

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  22 in total

1.  Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling.

Authors:  Huifen Chen; Bryan K Chan; Jason Drummond; Anthony A Estrada; Janet Gunzner-Toste; Xingrong Liu; Yichin Liu; John Moffat; Daniel Shore; Zachary K Sweeney; Thuy Tran; Shumei Wang; Guiling Zhao; Haitao Zhu; Daniel J Burdick
Journal:  J Med Chem       Date:  2012-06-01       Impact factor: 7.446

2.  (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD.

Authors:  C-Y Chen; Y-H Weng; K-Y Chien; K-J Lin; T-H Yeh; Y-P Cheng; C-S Lu; H-L Wang
Journal:  Cell Death Differ       Date:  2012-04-27       Impact factor: 15.828

3.  Kinase activity of mutant LRRK2 mediates neuronal toxicity.

Authors:  Wanli W Smith; Zhong Pei; Haibing Jiang; Valina L Dawson; Ted M Dawson; Christopher A Ross
Journal:  Nat Neurosci       Date:  2006-09-17       Impact factor: 24.884

4.  Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high-throughput screening.

Authors:  Franck Madoux; Xiaolin Li; Peter Chase; Gina Zastrow; Michael D Cameron; Juliana J Conkright; Patrick R Griffin; Scott Thacher; Peter Hodder
Journal:  Mol Pharmacol       Date:  2008-03-11       Impact factor: 4.436

Review 5.  Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson's disease.

Authors:  Payal N Gandhi; Shu G Chen; Amy L Wilson-Delfosse
Journal:  J Neurosci Res       Date:  2009-05-01       Impact factor: 4.164

Review 6.  Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease.

Authors:  Byoung Dae Lee; Valina L Dawson; Ted M Dawson
Journal:  Trends Pharmacol Sci       Date:  2012-05-09       Impact factor: 14.819

7.  Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2.

Authors:  David Ramonet; João Paulo L Daher; Brian M Lin; Klodjan Stafa; Jaekwang Kim; Rebecca Banerjee; Marie Westerlund; Olga Pletnikova; Liliane Glauser; Lichuan Yang; Ying Liu; Deborah A Swing; M Flint Beal; Juan C Troncoso; J Michael McCaffery; Nancy A Jenkins; Neal G Copeland; Dagmar Galter; Bobby Thomas; Michael K Lee; Ted M Dawson; Valina L Dawson; Darren J Moore
Journal:  PLoS One       Date:  2011-04-06       Impact factor: 3.240

8.  Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease.

Authors:  Byoung Dae Lee; Joo-Ho Shin; Jackalina VanKampen; Leonard Petrucelli; Andrew B West; Han Seok Ko; Yun-Il Lee; Kathleen A Maguire-Zeiss; William J Bowers; Howard J Federoff; Valina L Dawson; Ted M Dawson
Journal:  Nat Med       Date:  2010-08-22       Impact factor: 53.440

9.  Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2.

Authors:  Xianming Deng; Nicolas Dzamko; Alan Prescott; Paul Davies; Qingsong Liu; Qingkai Yang; Jiing-Dwan Lee; Matthew P Patricelli; Tyzoon K Nomanbhoy; Dario R Alessi; Nathanael S Gray
Journal:  Nat Chem Biol       Date:  2011-03-06       Impact factor: 15.040

10.  The selectivity of protein kinase inhibitors: a further update.

Authors:  Jenny Bain; Lorna Plater; Matt Elliott; Natalia Shpiro; C James Hastie; Hilary McLauchlan; Iva Klevernic; J Simon C Arthur; Dario R Alessi; Philip Cohen
Journal:  Biochem J       Date:  2007-12-15       Impact factor: 3.857
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  46 in total

1.  Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy.

Authors:  Jason Schapansky; Jonathan D Nardozzi; Fredrik Felizia; Matthew J LaVoie
Journal:  Hum Mol Genet       Date:  2014-03-27       Impact factor: 6.150

2.  LRRK2 secretion in exosomes is regulated by 14-3-3.

Authors:  Kyle B Fraser; Mark S Moehle; João P L Daher; Philip J Webber; Jeri Y Williams; Carrie A Stewart; Talene A Yacoubian; Rita M Cowell; Terje Dokland; Tong Ye; Dongquan Chen; Gene P Siegal; Robert A Galemmo; Elpida Tsika; Darren J Moore; David G Standaert; Kyoko Kojima; James A Mobley; Andrew B West
Journal:  Hum Mol Genet       Date:  2013-07-25       Impact factor: 6.150

3.  Synthesis and Preliminary Evaluation of [11 C]GNE-1023 as a Potent PET Probe for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson's Disease.

Authors:  Zhen Chen; Tuo Shao; Wei Gao; Hualong Fu; Thomas Lee Collier; Jian Rong; Xiaoyun Deng; Qingzhen Yu; Xiaofei Zhang; April T Davenport; James B Daunais; Hsiao-Ying Wey; Yihan Shao; Lee Josephson; Wen-Wei Qiu; Steven Liang
Journal:  ChemMedChem       Date:  2019-08-22       Impact factor: 3.466

Review 4.  Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications.

Authors:  Iakov N Rudenko; Mark R Cookson
Journal:  Neurotherapeutics       Date:  2014-10       Impact factor: 7.620

5.  Unique functional and structural properties of the LRRK2 protein ATP-binding pocket.

Authors:  Zhiyong Liu; Robert A Galemmo; Kyle B Fraser; Mark S Moehle; Saurabh Sen; Laura A Volpicelli-Daley; Lawrence J DeLucas; Larry J Ross; Jacob Valiyaveettil; Omar Moukha-Chafiq; Ashish K Pathak; Subramaniam Ananthan; Hollis Kezar; E Lucile White; Vandana Gupta; Joseph A Maddry; Mark J Suto; Andrew B West
Journal:  J Biol Chem       Date:  2014-09-16       Impact factor: 5.157

Review 6.  LRRK2 pathobiology in Parkinson's disease.

Authors:  Ian Martin; Jungwoo Wren Kim; Valina L Dawson; Ted M Dawson
Journal:  J Neurochem       Date:  2014-10-10       Impact factor: 5.372

Review 7.  The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease.

Authors:  Noémie Cresto; Camille Gardier; Francesco Gubinelli; Marie-Claude Gaillard; Géraldine Liot; Andrew B West; Emmanuel Brouillet
Journal:  Eur J Neurosci       Date:  2018-10-24       Impact factor: 3.386

8.  The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins.

Authors:  Mark S Moehle; João Paulo Lima Daher; Travis D Hull; Ravindra Boddu; Hisham A Abdelmotilib; James Mobley; George T Kannarkat; Malú G Tansey; Andrew B West
Journal:  Hum Mol Genet       Date:  2015-04-29       Impact factor: 6.150

9.  Enantioselective synthesis of atropisomeric benzamides through peptide-catalyzed bromination.

Authors:  Kimberly T Barrett; Scott J Miller
Journal:  J Am Chem Soc       Date:  2013-02-14       Impact factor: 15.419

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

Authors:  Bryan K Chan; Anthony A Estrada; Huifen Chen; John Atherall; Charles Baker-Glenn; Alan Beresford; Daniel J Burdick; Mark Chambers; Sara L Dominguez; Jason Drummond; Andrew Gill; Tracy Kleinheinz; Claire E Le Pichon; Andrew D Medhurst; Xingrong Liu; John G Moffat; Kevin Nash; Kimberly Scearce-Levie; Zejuan Sheng; Daniel G Shore; Hervé Van de Poël; Shuo Zhang; Haitao Zhu; Zachary K Sweeney
Journal:  ACS Med Chem Lett       Date:  2012-11-23       Impact factor: 4.345
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