BDF34019555
BDF34019555 is a blood-brain barrier-permeable binder targeting the conserved region (amino acid residues 320-340) of TDP-43, with a Kd of 10.4 μM for full-length TDP-43 and 7.8 μM for the CR polypeptide, respectively. BDF34019555 binds to the conserved α-helical region of TDP-43 in a Trp334-dependent manner, inhibits liquid-liquid phase separation, aggregation and mitochondrial localization of TDP-43, restores mitochondrial function, reduces cytoplasmic and insoluble TDP-43 levels, without affecting the splicing activity of TDP-43. BDF34019555 exerts neuroprotective effects, alleviates motor neuron loss and improves motor neuron function. BDF34019555 can be used in studies related to amyotrophic lateral sclerosis.
For research use only. We do not sell to patients.
- CAS No.: 2060801-74-1
- Formula: C19H24N6O
- Molecular Weight:352.43
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Protocols
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
Description
IC50 & Target
[1]|
TDP-43 10.4 μM (Kd, full-length TDP-43) |
TDP-43 7.8 μM (Kd, CR polypeptide) |
In Vitro
BDF34019555 (XL20) (3.125-50 μM) binds to full-length human TDP-43 in a CR-dependent manner, with an apparent KD of approximately 1.04 × 10-5 M[1].
BDF34019555 (3.125-50 μM) binds directly to the isolated human TDP-43 CR peptide, with an apparent KD value of approximately 7.84 × 10-6 M[1].
BDF34019555 (12.5-100 μM; 12 h) inhibits the aggregation of recombinant human TDP-43 LCD in a dose-dependent and CR-dependent manner[1].
BDF34019555 (6.25-100 μM; 18 h) dose-dependently inhibits the formation of basal and sodium arsenite-induced TDP-43 aggregates in HEK293 cells stably expressing EGFP-tagged human TDP-43, and this effect is dependent on CR[1].
BDF34019555 (20 μM; 30 min) increases the thermal stability of wild-type human TDP-43 in HEK293 cell lysates in a CR-dependent manner, confirming target binding[1].
BDF34019555 (100 μM; 18 h) reduces the mitochondrial localization of human TDP-43ΔNLS in HEK293 cells[1].
BDF34019555 (100 μM; 18 h) enhances mitochondrial respiratory capacity (maximal respiratory capacity and complex I-specific respiratory capacity) in HEK293 cells in a CR-dependent manner[1].
BDF34019555 (20 μM; 7 days) restores dendritic spine density, reduces cytoplasmic TDP-43 aggregation, and improves mitochondrial function in human induced pluripotent stem cell-derived TDP-43p.Gln331Lys motor neurons, without affecting cell viability[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:HEK293 cells
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Concentration:100 μM
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Incubation Time:18 h
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Result:Reduced the protein level of TDP-43 in mitochondrial fractions in HEK293 cells.
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Cell Line:HEK293 cells
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Concentration:100 μM
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Incubation Time:18 h
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Result:Significantly suppressed TDP-43 condensate formation in HEK293 cells stably expressing EGFP-TDP-43, with greater efficacy than XL21-XL27.
Significantly inhibited the colocalization/association of TDP-43 condensates with mitochondria in HEK293 cells expressing EGFP–TDP-43ΔNLS.
Parmacokinetics
In Vivo
BDF34019555 (XL20) (5-200 mg/kg; i.p.; single administration, 3 times per week for 1 month) exhibits favorable safety profiles in female wild-type C57BL/6J mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J (male and female, starting age 45 days, p.Ala315Thr hemizygous TDP-43 transgenic)[1]
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Dosage:50 mg/kg
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Administration:i.p.; three times weekly
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Result:Eliminated hindlimb clasping and enhanced rotarod test performance to levels similar to age-matched non-transgenic littermates.
Significantly alleviated gait abnormalities, as measured by stride length.
Increased lifespan of male p.Ala315Thr mice compared to vehicle-treated controls.
Significantly alleviated skeletal muscle atrophy (gastrocnemius muscle weight) and spinal motor neuron loss.
Suppressed cytoplasmic TDP-43 accumulation, reduced insoluble TDP-43 (including cleaved C-terminal fragments), and restored normal mitochondrial morphology in spinal cord neurons.
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Animal Model:C57BL/6J (female, adult)[1]
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Dosage:5 mg/kg (single dose); 50 mg/kg (single dose, repeated dose); 100 mg/kg (single dose); 200 mg/kg (single dose)
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Administration:i.p.; single dose, three times weekly for one month
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Result:Caused no animal deaths, no significant changes in body/organ weight, and no hematological or histopathological abnormalities at single doses of 50 mg/kg and 100 mg/kg.
Caused one death on day 10, along with decreased body weight gain and food intake in the 200 mg/kg single-dose group.
Caused no changes in body weight gain at repeated doses of 50 mg/kg three times weekly for one month.
Demonstrated good CNS penetration, with brain-to-plasma concentration ratios averaging above 0.5 and spinal-to-plasma ratios approaching 0.8 at a 50 mg/kg dose.
Chemical Information
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CAS No. 2060801-74-1
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Molecular Weight 352.43
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Formula C19H24N6O
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SMILES
CN([C@@H]1[C@H](O)[C@@H](N2C=NC3=C(N)N=CN=C32)CCC1)CC4=CC=CC=C4
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocols
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Mitochondrial membrane-potential fluorescent assay
Mitochondrial membrane potential fluorescent assays estimate ΔΨm in living cells using lipophilic cationic dyes such as TMRM, TMRE, rhodamine 123, and JC-1, which accumulate in mitochondria according to membrane polarization; loss of signal after FCCP or CCCP treatment is interpreted as mitochondrial depolarization. TMRM/TMRE and rhodamine 123 are commonly used for semi-quantitative live-cell microscopy or flow cytometry, while JC-1 can report a shift from red aggregate fluorescence to green monomer fluorescence during depolarization; interpretation requires controls because dye concentration, quenching mode, cell type, dye efflux, and mitochondrial mass can affect fluorescence independently of ΔΨm.
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Mitochondrial membrane-potential and mitochondrial mass staining
Mitochondrial membrane potential staining measures the electrochemical polarization across the mitochondrial inner membrane in live cells using lipophilic cationic fluorescent probes; early rhodamine-based work showed that selective mitochondrial dye accumulation is lost when the mitochondrial transmembrane potential is dissipated. JC-1 reports mitochondrial polarization by shifting from green monomer fluorescence to red J-aggregate fluorescence as dye concentration increases within energized mitochondria; therefore, the red/green fluorescence ratio is used as a relative readout of mitochondrial membrane potential. TMRE or TMRM staining provides a single-channel relative readout because these cationic rhodamine esters accumulate in polarized mitochondria, and lower fluorescence indicates reduced mitochondrial polarization when acquisition and dye-loading conditions are controlled. Mitochondrial mass staining is commonly performed with MitoTracker Green FM or related MitoTracker dyes as
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
BDF34019555 Related Classifications
HY-187172 Related Classifications
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