TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis : evidence from druggable genome Mendelian randomization and pharmacological verification in vitro
© 2024. The Author(s)..
BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.
METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.
RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.
CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
|---|---|
| Enthalten in: |
BMC medicine - 22(2024), 1 vom: 05. März, Seite 96 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Duan, Qing-Qing [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.03.2024 Date Revised 08.03.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1186/s12916-024-03314-1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369338146 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369338146 | ||
| 003 | DE-627 | ||
| 005 | 20240308232746.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240306s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12916-024-03314-1 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1320.xml |
| 035 | |a (DE-627)NLM369338146 | ||
| 035 | |a (NLM)38443977 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Duan, Qing-Qing |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis |b evidence from druggable genome Mendelian randomization and pharmacological verification in vitro |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.03.2024 | ||
| 500 | |a Date Revised 08.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment | ||
| 520 | |a METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models | ||
| 520 | |a RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation | ||
| 520 | |a CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Amyotrophic lateral sclerosis | |
| 650 | 4 | |a Drug repurposing | |
| 650 | 4 | |a Druggable gene | |
| 650 | 4 | |a Mendelian randomization | |
| 650 | 4 | |a TBK1 | |
| 650 | 7 | |a amlexanox |2 NLM | |
| 650 | 7 | |a BRL1C2459K |2 NLM | |
| 650 | 7 | |a TBK1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 700 | 1 | |a Wang, Han |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Wei-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Xiao-Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Xiao-Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Zheng |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Yan-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guo-Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yong-Ping |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t BMC medicine |d 2003 |g 22(2024), 1 vom: 05. März, Seite 96 |w (DE-627)NLM143503421 |x 1741-7015 |7 nnns |
| 773 | 1 | 8 | |g volume:22 |g year:2024 |g number:1 |g day:05 |g month:03 |g pages:96 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12916-024-03314-1 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 22 |j 2024 |e 1 |b 05 |c 03 |h 96 | ||