BI-78D3

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种小分子 JIP1 模拟物，作为 JNK 的底物竞争性抑制剂，IC50 为 500 nM。

A small molecule JIP1 mimic that functions as substrate competitive inhibitor of JNK with IC50 of 500 nM; targets the JNK-JIP interaction site and dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell; blocks JNK dependent Con A-induced liver damage, restores insulin sensitivity in mouse models of type 2 diabetes.

BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. BI-78D3 is able to compete with the D-domain of JIP1 (amino acids 153-163; pepJIP1) for JNK1 binding (IC50=500 nM). Using the same in vitro LanthaScreen kinase assay and the same ATF2 substrate, BI-78D3 is found to be 100-fold less active vs. p38α, a member of the MAPK family with high structural similarity to JNK, and completely inactive against mTOR and PI3-kinase (α-isoform), both unrelated protein kinases. Furthermore, Lineweaver-Burk analysis clearly indicates that BI-78D3 is competitive with ATF2 for binding to JNK1 with an apparent Ki value of 200 nM. In an attempt to profile the properties of BI-78D3 in the context of a complex cellular milieu, the cell-based LanthaScreen kinase assay is used. In this assay BI-78D3 is able to inhibit TNF-α stimulated phosphorylation of c-Jun in cell (EC50=12.4 μM).

The link between ConA-induced liver failure, TNF receptor signaling, and JNK function has been established by studies employing JNK1-/- and JNK2-/- mice. For this analysis, insulin insensitive mice are injected only once with 25 mg/kg BI-78D3, 30 min before insulin injection. The effect of insulin on blood glucose levels is then measured. BI-78D3 results in a statistically significant reduction in blood glucose levels as compared with the vehicle control. Thus, the ability of BI-78D3 to abrogate ConA-induced liver damage and restore insulin sensitivity is consistent with its proposed function as an effective JNK inhibitor. Liquid chromatography/mass spectrometry bio-availability analysis demonstrates that BI-78D3 has favorable microsome and plasma stability (T1/2=54 min).

BI 78D3 | BI78D3

MAPK/ERK Signaling

JNK

JNK

Cancer

——

883065-90-5

379.37106

C13H9N5O5S2

>98% (HPLC)

DMSO: ≥ 31 mg/mL

O=C1NN=C(SC2=NC=C([N+]([O-])=O)S2)N1C3=CC=C(OCCO4)C4=C3

3H-1,2,4-Triazol-3-one, 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,4-dihydro-5-[(5-nitro-2-thiazolyl)thio]-

(-20℃)

With Ice Pack

≥ 2 years