Biochem/physiol Actions

Reversible: yes

Primary TargetBDK

Cell permeable: yes

General description

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.

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.

Legal Information

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

Other Notes

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

Packaging

Packaged under inert gas

10 mg in Glass bottle

Reconstitution

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.

Warning

Toxicity: Standard Handling (A)