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.
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- Formule: C19H24N6O
- Masse moléculaire:352.43
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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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TDP-43 10.4 μM (Kd, full-length TDP-43) |
TDP-43 7.8 μM (Kd, CR polypeptide) |
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.
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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.
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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Masse moléculaire 352.43
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Formule C19H24N6O
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SMILES
CN([C@@H]1[C@H](O)C(N2C=NC3=C(N)N=CN=C32)CCC1)CC4=CC=CC=C4
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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.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
BDF34019555 Related Classifications
HY-187172 Related Classifications
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