EBP1 INHIBITOR WS6 (C15-1304-241)

General description

A cell-permeable phenoxypyrimidin-cyclopropanecarboxamide compound that effectively stimulates the growth of primary β cells in cultured primary rat and human islets in vitro (EC_max in 4 d = 200 and 400 nM, respectively) and in the murine type 1 diabetes (T1D) model RIP-DTA in vivo (170% of control pancreas Ki-67-positive β cells in 1 wk; 5 mg/kg i.p. q.o.d.) by interacting with IKKε and EBP1/PA2G4/Erb3 binding protein-1 and blocking the known suppressor function of EBP1 toward E2F-mediated transcription. Likewise, dual inhibition of EBP1 (with shRNA) and IKK (1 µM; Cat. Nos. 401486 & 505378) is shown to fully recapitulate the proliferating effect of WS6 in R7T1 cells.

A cell-permeable phenoxypyrimidin-cyclopropanecarboxamide compound that effectively stimulates the growth of primary β cells in cultures in vitro (EC_max in 4 d = 200 and 400 nM, respectively, for increasing Ki-67-positive β cell population in primary rat and human islets) and in the murine type 1 diabetes (T1D) model RIP-DTA in vivo (170% of control pancreas Ki-67-positive β cells in 1 wk and 150% of control pancreas β cell mass in 6 wks; 5 mg/kg i.p. q.o.d.) with significant blood glucose reducing efficacy (200 vs. 425 mg/dL on d45 with or without treatment). WS6 is shown to interact with IKKε and EBP1/PA2G4/Erb3 binding protein-1 as well as upregulate cellular E2F mRNA (2.8- and 4.8-fold of vehicle control, respectively, with 8 h and 12 h treatment; 1 µM) and transcription activity (1.4- and 1.5-fold of vehicle control, respectively, at 0.74 and 2.22 µM; 24 h treatment) in murine β cell line R7T1, consistent with blocking the known suppressor function of EBP1 toward E2F-mediated transcription. Likewise, dual inhibition of EBP1 (with shRNA) and IKK (1 µM; Cat. Nos. 401486 & 505378) is shown to fully recapitulate the proliferating effect of WS6 in R7T1 cells.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
EBP1/PA2G4/Erb3 binding protein-1

Reversible: yes

Secondary Target
IKKε

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 6 months at -20°C.

Other Notes

Shen, W., et al. 2013. J. Am. Chem. Soc.135, 1669.

Legal Information

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

Molecular Weight: 568.59 (free base basis). Empirical Formula: C₂₉H₃₁F₃N₆O₃ · xHCl. Assay: ≥. 98% (HPLC). Quality Level: 100. form: powder. manufacturer/tradename: Calbiochem^®. . storage condition: OK to freeze, desiccated (hygroscopic), protect from light. color: white. solubility: DMSO: 100 . mg/mL, water: 100 . mg/mL. storage temp.: −. 20°C. SMILES string: CN1CCN(CC1)CC2: C(C: C(C: C2)NC(: O)CC3: CC: C(C: C3)OC4: NC: NC(: C4)NC(: O)C5CC5)C(F)(F)F. Storage Class Code: 11 - Combustible Solids. WGK: WGK 3. Flash Point(F): Not applicable. Flash Point(C): Not applicable.