半岛bd体育手机客户端 说明

一般描述

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 ?M) due to much optimized affinity toward the BDK N-terminal allosteric site (Kd = 2.4 vs. 5.7 ?M) 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.
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.

生化/生理作用

Cell permeable: yes
Reversible: yes
Primary Target
BDK

包装

Packaged under inert gas

警告

Toxicity: Standard Handling (A)

重悬

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

其他说明

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

法律信息

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

基本信息

半岛bd体育手机客户端 性质

安全信息