Sigma-Aldrich Bdk Inhibitor Ii (S)-Cpp

Assay

≥98% (HPLC)

Quality Level

100

Form

oil

Manufacturer/Tradename

Calbiochem^®

Storage Condition

OK to freeze
desiccated
protect from light

Color

clear colorless

Solubility

DMSO: 100 mg/mL

Storage Temp.

−20°C

General Description

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 lowin vivoclearance , 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 stabilityin vitro(half-life = 3.1 H and 6.8 H using murine liver S9 preparation or murine hepatocytes, respectively) and low clearancein 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.

Biochem/Physiol Actions

Cell permeable: yesPrimary Target
BDKReversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

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.

Other Notes

Tso, S.C., et Al. 2013.Proc. Natl. Acad. Sci. USA 110,9728.CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany