WO2008091799A3 - Cell-based methods for identifying inhibitors of parkinson's disease-associated lrrk2 mutants - Google Patents
Cell-based methods for identifying inhibitors of parkinson's disease-associated lrrk2 mutants Download PDFInfo
- Publication number
- WO2008091799A3 WO2008091799A3 PCT/US2008/051485 US2008051485W WO2008091799A3 WO 2008091799 A3 WO2008091799 A3 WO 2008091799A3 US 2008051485 W US2008051485 W US 2008051485W WO 2008091799 A3 WO2008091799 A3 WO 2008091799A3
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lrrk2
- inhibitors
- parkinson
- disease
- methods
- Prior art date
Links
- 208000018737 Parkinson disease Diseases 0.000 title abstract 6
- 239000003112 inhibitor Substances 0.000 title abstract 6
- 238000000034 method Methods 0.000 title abstract 4
- 101000941879 Homo sapiens Leucine-rich repeat serine/threonine-protein kinase 2 Proteins 0.000 abstract 5
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 abstract 5
- 230000003834 intracellular effect Effects 0.000 abstract 2
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 abstract 1
- 101710113864 Heat shock protein 90 Proteins 0.000 abstract 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 abstract 1
- 229940124786 LRRK2 inhibitor Drugs 0.000 abstract 1
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 abstract 1
- 102000009784 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Human genes 0.000 abstract 1
- 206010029350 Neurotoxicity Diseases 0.000 abstract 1
- 206010044221 Toxic encephalopathy Diseases 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 abstract 1
- 230000003247 decreasing effect Effects 0.000 abstract 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 abstract 1
- 230000002068 genetic effect Effects 0.000 abstract 1
- 230000035772 mutation Effects 0.000 abstract 1
- 208000015122 neurodegenerative disease Diseases 0.000 abstract 1
- 230000007135 neurotoxicity Effects 0.000 abstract 1
- 231100000228 neurotoxicity Toxicity 0.000 abstract 1
- 229940124606 potential therapeutic agent Drugs 0.000 abstract 1
- 238000007423 screening assay Methods 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
- C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/26—Oils; Viscous liquids; Paints; Inks
- G01N33/28—Oils, i.e. hydrocarbon liquids
- G01N33/2811—Oils, i.e. hydrocarbon liquids by measuring cloud point or pour point of oils
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Urology & Nephrology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Food Science & Technology (AREA)
- Neurology (AREA)
- General Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). PD-associated LRRK2 mutants induce the formation of intracellular filaments which can be visualized and quantified. The invention provides cell- based screening assays and methods for identifying inhibitors of PD-associated LRRK2 mutants. Inhibitors can be identified by assessing intracellular distribution of LRRK2 protein. Identified inhibitors are potential therapeutic agents which may be useful for treating PD or other neurodegenerative disorders. The methods of the invention were used to identify 14-3-3Θ and the inhibitor of HSP90 geldanamycin, as inhibitors of LRRK2 toxicity in cells. The invention provides methods for preventing or decreasing neurotoxicity in a subject by administering a LRRK2 inhibitor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88167707P | 2007-01-22 | 2007-01-22 | |
| US60/881,677 | 2007-01-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008091799A2 WO2008091799A2 (en) | 2008-07-31 |
| WO2008091799A3 true WO2008091799A3 (en) | 2008-11-27 |
Family
ID=39645106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2008/051485 WO2008091799A2 (en) | 2007-01-22 | 2008-01-18 | Cell-based methods for identifying inhibitors of parkinson's disease-associated lrrk2 mutants |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008091799A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9149506B2 (en) | 2012-04-02 | 2015-10-06 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding septin-4 |
| US9221891B2 (en) | 2012-04-02 | 2015-12-29 | Moderna Therapeutics, Inc. | In vivo production of proteins |
| US9447164B2 (en) | 2010-08-06 | 2016-09-20 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8206942B2 (en) | 2007-04-05 | 2012-06-26 | Medical Research Council | Methods of identifying LRRK2 inhibitors |
| GB0706709D0 (en) | 2007-04-05 | 2007-05-16 | Medical Res Council | Methods |
| GB2463656B (en) * | 2008-09-18 | 2010-10-13 | Medical Res Council | Substrate of LRRK2 and methods of assessing LRRK2 activity |
| US20110256553A1 (en) * | 2010-04-19 | 2011-10-20 | Nichols R Jeremy | Methods |
| US8367349B2 (en) * | 2010-04-19 | 2013-02-05 | Medical Research Council | Methods for identifying modulators of LRRK2 |
| GB2479799B (en) * | 2010-04-19 | 2012-09-19 | Medical Res Council | Methods for assessing LRRK2 inhibitors |
| DE19177059T1 (en) | 2010-10-01 | 2021-10-07 | Modernatx, Inc. | RIBONUCLEIC ACID CONTAINING N1-METHYL-PSEUDOURACILE AND USES |
| JP2014504362A (en) * | 2010-11-30 | 2014-02-20 | ジェネンテック， インコーポレイテッド | Assays and biomarkers for LRRK2 |
| DE12722942T1 (en) | 2011-03-31 | 2021-09-30 | Modernatx, Inc. | RELEASE AND FORMULATION OF MANIPULATED NUCLEIC ACIDS |
| US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| JP6113737B2 (en) | 2011-10-03 | 2017-04-12 | モデルナティエックス インコーポレイテッドＭｏｄｅｒｎａＴＸ，Ｉｎｃ． | Modified nucleosides, nucleotides and nucleic acids and methods for their use |
| MX2014007233A (en) | 2011-12-16 | 2015-02-04 | Moderna Therapeutics Inc | Modified nucleoside, nucleotide, and nucleic acid compositions. |
| US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
| US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
| KR20150027267A (en) | 2012-06-29 | 2015-03-11 | 화이자 인코포레이티드 | NOVEL 4-(SUBSTITUTED-AMINO)-7H-PYRROLO[2,3-d]PYRIMIDINES AS LRRK2 INHIBITORS |
| CA2892529C (en) | 2012-11-26 | 2023-04-25 | Moderna Therapeutics, Inc. | Terminally modified rna |
| JP2016504050A (en) * | 2013-01-17 | 2016-02-12 | モデルナ セラピューティクス インコーポレイテッドＭｏｄｅｒｎａ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． | Signal sensor polynucleotide for modification of cell phenotype |
| US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
| WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
| CA2926218A1 (en) | 2013-10-03 | 2015-04-09 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| WO2015092592A1 (en) | 2013-12-17 | 2015-06-25 | Pfizer Inc. | Novel 3,4-disubstituted-1h-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7h-pyrrolo[2,3-c]pyridazines as lrrk2 inhibitors |
| MX2018003215A (en) | 2015-09-14 | 2018-06-08 | Pfizer | Novel imidazo [4,5-c] quinoline and imidazo [4,5-c][1,5] naphthyridine derivatives as lrrk2 inhibitors. |
| AU2016336344A1 (en) | 2015-10-05 | 2018-04-19 | Modernatx, Inc. | Methods for therapeutic administration of messenger ribonucleic acid drugs |
| WO2017120365A1 (en) | 2016-01-05 | 2017-07-13 | Ionis Pharmaceuticals, Inc. | Methods for reducing lrrk2 expression |
| MX2020013653A (en) | 2018-06-27 | 2021-03-02 | Ionis Pharmaceuticals Inc | Compounds and methods for reducing lrrk2 expression. |
| EP3769768A1 (en) | 2019-07-23 | 2021-01-27 | Consejo Superior de Investigaciones Cientificas (CSIC) | Compounds useful for the treatment of parkinson s disease |
| EP3872170A1 (en) * | 2020-02-25 | 2021-09-01 | University of Georgia Research Foundation, Inc. | Chemically-stabilized allosteric modulators of leucine-rich repeat kinase 2 (lrrk2) |
| CN112029738B (en) * | 2020-08-18 | 2022-04-29 | 浙江省人民医院 | Human parkin protein acetylation and application thereof in medicine preparation |
| CN113999847A (en) * | 2021-10-11 | 2022-02-01 | 中山大学附属第六医院 | sgRNA of specific target LRRK2 gene, lentivirus transfection vector and application thereof |
-
2008
- 2008-01-18 WO PCT/US2008/051485 patent/WO2008091799A2/en active Application Filing
Non-Patent Citations (2)
| Title |
|---|
| BELIN ET AL.: "Parkinson's disease: a genetic perspective", FEBS J., vol. 275, no. 7, April 2008 (2008-04-01), pages 1377 - 1383 * |
| LU ET AL.: "Molecular biology changes associated with LRRK2 mutations in Parkinson's disease", J. NEUROSCI. RES., vol. 86, no. 9, July 2008 (2008-07-01), pages 1895 - 1901 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9447164B2 (en) | 2010-08-06 | 2016-09-20 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| US9149506B2 (en) | 2012-04-02 | 2015-10-06 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding septin-4 |
| US9221891B2 (en) | 2012-04-02 | 2015-12-29 | Moderna Therapeutics, Inc. | In vivo production of proteins |
| US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
| US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008091799A2 (en) | 2008-07-31 |
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