5.05602

BDK Inhibitor II, (S)-CPP

• Synonim(y): BDK Inhibitor II, (S)-CPP, (S)-α-Chloro-phenylpropionic acid, BCKD Kinase Inhibitor II, Branched-Chain α-Ketoacid Dehydrogenase Kinase Inhibitor II, BCKD Kinase Inhibitor II, Branched-Chain α-Ketoacid Dehydrogenase Kinase Inhibitor II, (S)-α-Chloro-phenylpropionic acid
• Wzór empiryczny (zapis Hilla): C₉H₉ClO₂
• Numer CAS: 41998-38-3
• Masa cząsteczkowa: 184.62
• Kod UNSPSC: 12352200
• NACRES: NA.77

Właściwości

• Próba: ≥98% (HPLC)
• Poziom jakości: 100
• Postać: oil
• producent / nazwa handlowa: Calbiochem^®
• warunki przechowywania: OK to freeze; desiccated; protect from light
• kolor: clear colorless
• rozpuszczalność: DMSO: 100 mg/mL
• temp. przechowywania: −20°C

Opis

Opis ogólny

A cell-permeable chlorophenylpropionate compound that is superior to its structural analog 4PB (Cat. No. 567616) as an inhibitor against mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC) regulatory kinase BDK (BCKD kinase; IC₅₀ = 6.3 vs. 53.1 M) due to much optimized affinity toward the BDK N-terminal allosteric site (Kd = 2.4 vs. 5.7 M), effectively blocking BDK substrate access by preventing BDK interaction with the homo-24-meric dihydrolipoyltransferase BCKDC E2 component, while exhibiting little potency against PDK2 or BCKD phosphatase BDP even at concentrations as high as 1 mM (<10% inhibition). Shown to effectively reduce E1-α Ser293 phosphorylation with concomitant BCKDC activity upregulation in multiple tissues in mice (ED_max =160 mg/kg via i.p.) in vivo. Despite good stability and low in vivo clearance , high doses are recommended for mice treatment due to low tissue penetration efficiency.

A cell-permeable chlorophenylpropionate compound that is superior to its structural analog 4PB (Cat. No. 567616) as an inhibitor against mitochondrial BCKDC (branched-chain α-ketoacid dehydrogenase complex) regulatory kinase BDK (BCKD kinase; IC₅₀ = 6.3 vs. 53.1 µM) due to much optimized affinity toward the BDK N-terminal allosteric site (Kd = 2.4 vs. 5.7 µM) via carboxylate oxygens-mediated hydrogen bonds, as well as hydrophobic interactions mediated by the α-chlorine and the phenyl ring, effectively blocking BDK substrate access by preventing BDK interaction with the homo-24-meric dihydrolipoyltransferase BCKDC E2 component, while exhibiting little potency against PDK2 (pyruvate dehydrogenase kinase isoform 2) or BDP (BCKD phosphatase) even at concentrations as high as 1 mM (<10% inhibition). Shown to effectively reduce E1-α Ser293 phosphorylation with concomitant BCKDC activity upregulation in multiple tissues in mice (ED_max =160 mg/kg via i.p.; 60 min) in vivo, resulting in significant downregulation of serum BCAA (branched-chain amino acid) Leu/Ile and Val levels. Pharmacokinetic studies reveal good stability in vitro (half-life = 3.1 h and 6.8 h using murine liver S9 preparation or murine hepatocytes, respectively) and low clearance in vivo (CL/F = 0.113 mL/min; 40 mg/kg i.p.), however the compound does not penetrate tissues efficiently (V_Z/F = 20.8 mL; 40 mg/kg i.p.) and high dosages are recommended for mice treatment.

Działania biochem./fizjol.

Cell permeable: yes

Primary Target
BDK

Reversible: yes

Opakowanie

Packaged under inert gas

Ostrzeżenie

Toxicity: Standard Handling (A)

Rekonstytucja

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 1 month at -20°C.

Use only fresh DMSO for reconstitution.

Inne uwagi

Tso, S.C., et al. 2013. Proc. Natl. Acad. Sci. USA110, 9728.

Informacje prawne

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

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Informacja o środkach bezpieczeństwa

• Kod klasy składowania: 11 - Combustible Solids
• Klasa zagrożenia wodnego (WGK): WGK 3
• Temperatura zapłonu (°F): Not applicable
• Temperatura zapłonu (°C): Not applicable