ATB1071
ATB1071 is a brain-penetrant and orally active p62/SQSTM1 activator. ATB1071 binds to the p62-ZZ domain, promotes PB1-dependent p62 self-polymerization, and activates p62-mediated mitophagy. ATB1071 can be used for the research of Leigh syndrome, cerebral ischemia-reperfusion injury[1].
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- CAS No.: 2921556-65-0
- Formule: C25H27F2NO4
- Masse moléculaire:443.48
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
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Activité biologique
Description
In Vitro
ATB1071 (1 mM; 2 h) engages the p62-ZZ domain to promote PB1-dependent p62 oligomerization in HeLa cell lysates[1].
ATB1071 activates p62-dependent selective autophagy in SH-SY5Y cells without engaging canonical AMPK activation or mTOR inhibition[1].
ATB1071 (2.5-10 μM) induces p62-dependent, autophagy-lysosome-mediated clearance of damaged mitochondria selectively under mitochondrial stress in SH-SY5Y cells, with dose-dependent activity at 2.5-10 μM[1].
ATB1071 induces mitophagy in mt-mKeima HeLa cells via a Parkin-independent pathway under Rotenone (HY-B1756)-induced stress, and enhances Parkin-mediated mitophagy under CCCP (HY-100941)-induced stress[1].
ATB1071 activates mitophagy and restores mitochondrial bioenergetic function in NDUFS4-knockdown SH-SY5Y cells, reversing MMP depolarization, ROS elevation, and ATP deficiency[1].
ATB1071 (2-5 μM; 8-24 h) enhances the interaction between p62 and NIPSNAP1 in HEK293T cells, particularly under mitochondrial stress, via a mechanism dependent on the p62 ZZ/PB1 axis[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
Parmacokinetics
| Species | Dose | Route | AUClast | T1/2 | Bioavailability | Brain-to-Plasma Ratio |
|---|---|---|---|---|---|---|
| Mice[1] | 10 mg/kg | p.o. | 5750.6 ng·h/mL | 9.8 h | 70.4 % | 2.12 % |
In Vivo
ATB1071 (10 mg/kg; i.p.; at 0, 3, 24, and 48 hours post-MCAO) provides robust neuroprotection and restores neurological function after cerebral ischemia-reperfusion injury primarily via EBP1-dependent mitophagy[1].
ATB1071 (10 mg/kg; i.p.; at 0, 3, 24, and 48 hours post-MCAO) has its mediated mitophagy restored by reintroduction of EBP1, which enhances neuroprotection and functional recovery after cerebral ischemia-reperfusion injury in Ebp1-deficient mice[1].
ATB1071 (p.o.; daily for 1 week or 3 times per week for 2 weeks) exhibits NOAEL of at least 30 mg/kg and 300 mg/kg in ICR mice and rats, respectively[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:B6.129S4-Ndufs4m1.1Rpa/J mice (Ndufs4-/-; starting at postnatal day 10); wild-type/heterozygous control mice (starting at postnatal day 10)[1]
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Dosage:10 mg/kg
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Administration:i.p.; every other day; 40 days
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Result:Increased TOM20+LC3+ proximity ligation assay puncta in the deep cerebellar nuclei and olfactory bulb of Ndufs4-/- mice.
Elevated p62 levels by ~1.8-fold and its oligomeric/aggregated species by ~2.4-fold in the brain mitochondrial fraction.
Reduced GFAP+ astrocytes and Iba1+ microglia.
Lowered expression of inflammation-associated genes (Cd14, Il-1β, S100a8).
Extended median survival by ~31% and maximal lifespan by ~64% relative to vehicle-treated Ndufs4-/- mice.
Improved forelimb grip strength by ~34% at postnatal day 40.
Increased rotarod latency to fall by ~3-fold at postnatal day 50.
Delayed the onset of clasping/twisting by ~12%.
Reduced skin inflammation-associated hair loss severity scores from 2 to 1.22 at postnatal day 20.
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Animal Model:Pa2g4flox/flox mice (control; aged 6-8 weeks); CamK2-Cre;Pa2g4flox/flox mice (neuron-specific Ebp1 knockout, Ebp1 CKO; aged 6-8 weeks)[1]
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Dosage:10 mg/kg
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Administration:i.p.; at 0, 3, 24, and 48 hours post-MCAO
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Result:Decreased TOM20 levels, increased p62 and LC3-II levels, and enhanced recruitment of LC3+ phagophores to TOM20+ mitochondria in the hippocampus of control MCAO mice.
Reduced infarct volume by ~85% in control MCAO mice.
Lowered neuronal death in the CA1 region by ~91% in control MCAO mice.
Increased rotarod latency to fall from 54.7 to 207.4 seconds in control MCAO mice.
Enhanced four-limb grip strength by ~1.3-fold and forelimb grip strength by ~1.6-fold in control MCAO mice.
Increased total open-field travel distance from 1919 to 2579 cm in control MCAO mice.
Raised Y-maze spontaneous alternation rate from 53% to 83% in control MCAO mice.
Blunted effects in Ebp1 CKO mice, with only ~46% infarct volume reduction, ~40% neuronal death reduction, and no significant improvements in motor, behavioral, or cognitive functions.
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Animal Model:CamK2-Cre;Pa2g4flox/flox mice (neuron-specific Ebp1 knockout, Ebp1 CKO; aged 6-8 weeks)[1]
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Dosage:10 mg/kg
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Administration:i.p.; at 0, 3, 24, and 48 hours post-MCAO
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Result:Restored ATB1071-induced mitophagy in Ebp1 CKO mice via EBP1 reintroduction, as shown by increased LC3 and p62 levels and enhanced mitochondrial localization of LC3 in the hippocampus.
Reduced infarct volume by ~67% (vs ~52% in mock-expressing mice).
Lowered neuronal death by ~86% relative to the mock group.
Improved rotarod performance by ~2.2-fold.
Increased four-limb grip strength by ~1.5-fold and forelimb grip strength by ~1.5-fold.
Increased ambulatory activity by ~1.5-fold.
Improved working memory by ~33% compared with mock-expressing Ebp1 CKO mice.
Chemical Information
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CAS No. 2921556-65-0
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Masse moléculaire 443.48
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Formule C25H27F2NO4
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SMILES
OCCNCCCOC1=CC(OCC2=CC=C(F)C=C2)=C(OCC3=CC=C(F)C=C3)C=C1
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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Autophagy
Autophagy is a process in which eukaryotic cells use lysosomes to degrade their own cytoplasmic proteins and damaged organelles under the regulation of autophagy related gene (Atg). Microtubule-associated proteins light chain 3 (LC3) is recognized as autophagy marker, which transfers from cytoplasmic LC3 (LC3-I) to membrane type (LC3-II). LC3-II/I ratio could be detected by Western Blot and fluorescence microscopy.
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Mitophagy Solutions
Mitophagy is the selective autophagic degradation of mitochondria and functions as a mitochondrial quality-control pathway that removes damaged, depolarized, excess, or developmentally programmed mitochondria. The pathway links mitochondrial damage recognition, autophagosome recruitment, lysosomal delivery, and mitochondrial turnover to phenotypes such as mitochondrial homeostasis, oxidative-stress control, metabolic remodeling, differentiation, and neurodegeneration-related mitochondrial fidelity. The best-characterized damage-induced pathway is the PINK1-Parkin axis. Parkin is recruited selectively to impaired mitochondria and promotes their autophagic elimination, while mitochondrial depolarization stabilizes PINK1 on damaged mitochondria, recruits Parkin, and activates Parkin-dependent mitophagy. PINK1 also phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity, and PINK1-driven ubiquitin phosphorylation creates a feed-forward signal for recruiting autophagy machi
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Macroautophagy Solutions
Macroautophagy is a conserved lysosome-dependent degradation pathway in which cytoplasmic material is sequestered into double-membrane autophagosomes and delivered to lysosomes for degradation and recycling. The pathway supports cellular homeostasis during nutrient limitation, organelle stress, protein-aggregate accumulation, infection, differentiation, and tissue remodeling by coupling cargo sequestration, autophagosome maturation, lysosomal fusion, and degradation of cargo-derived macromolecules. The core molecular sequence includes initiation by nutrient- and stress-regulated autophagy machinery, autophagosome nucleation, LC3/ATG8-family conjugation to autophagosomal membranes, cargo selection through receptors such as SQSTM1/p62, autophagosome-lysosome fusion, and lysosomal degradation. LC3 was identified as a mammalian homolog of yeast Atg8 that localizes to autophagosomal membranes after processing, and p62/SQSTM1 was shown to connect ubiquitinated cargo with autophagic degradati
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
ATB1071 Related Classifications
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