PTP Inhibitor XXXI, II-B08 - Calbiochem (C15-1305-828)

General description

A cell-permeable indolo-salicylic acid compound that is shown to target SHP2 catalytic domain and inhibit SHP2-catalyzed pNPP hydrolysis (IC₅₀ = 5.5 µM) in a reversible and non-competitive manner (K_i = 5.2 µM), exhibiting 2.6- to 5.7-fold selectivity over PTP1B, SHP1, FAP1, Lyp, CD45, and LMWPTP (IC₅₀ = 14.3, 15.7, 20.3, 25.0, 30.0, and 31.1 µM, respectively) and >9-fold selectivity over Cdc14A, HePTP, LAR, PTPα, and VHR (IC₅₀ >50 µM). Effectively blocks hyperproliferative activity of human hematopoietic progenitor cells (Effective conc. = 10 µM) due to SHP2 mutations (D61Y and E76K) or GM-CSF stimulation, as well as c-kit-dependent (via ligand stimulation or D814V mutation), SHP2-mediated myeloid proliferation (Effective conc. = 5 to 75 µM). Dual PI-3K and SHP2 inhibition by LY294002 (Cat. Nos. 440202 & 440204) and II-B08 (10 mg/kg and 50 mg/kg, respectively; daily i.p.) is shown to greatly prolong the survival rate in a D814V KIT-expressing 32D-based murine MPD (myeloproliferative disease) model (0% survival rate on day 23, 27, 28, respectively, with DMSO, LY294002, II-B08 treatment alone; 20% survival rate on day 65 with combined treatment) in vivo.

A cell-permeable indolo-salicylic acid compound that is shown to target SHP2 catalytic domain and inhibit SHP2-catalyzed pNPP hydrolysis (IC₅₀ = 5.5 µM) in a reversible and non-competitive manner (K_i = 5.2 µM), exhibiting 2.6- to 5.7-fold selectivity over PTP1B, SHP1, FAP1, Lyp, CD45, and LMWPTP (IC₅₀ = 14.3, 15.7, 20.3, 25.0, 30.0, and 31.1 µM, respectively). Effectively blocks SHP2-mediated human hematopoietic progenitor cell hyperproliferation (10 µM) due to SHP2 mutations (D61Y and E76K) or GM-CSF stimulation, as well as c-kit-dependent (due to D814V mutation or via ligand stimulation), SHP2-mediated myeloid proliferation (5 to 75 µM). Dual PI-3K and SHP2 inhibition by LY294002 (Cat. Nos. 440202 & 440204) and II-B08 (10 mg/kg and 50 mg/kg, respectively; daily i.p.) is shown to greatly prolong the survival rate of mice bearing D814V KIT-expressing 32D cells in vivo.

Biochem/physiol Actions

Primary Target
SHP2

Reversible: yes

Secondary Target
Other PTPs

Target IC₅₀: 5.5, 9.0 and 10.8 &micro

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

Mali, R.S., et al. 2012. Blood120, 2669.
Zhang, X., et al. 2010. J. Med. Chem.53, 2482.

Legal Information

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

Molecular Weight: 557.60. Empirical Formula: C₃₃H₂₇N₅O₄. Quality Level: 200. Assay: ≥. 98% (HPLC). form: powder. potency: 5.2 . μ. M K_i. manufacturer/tradename: Calbiochem^®. . storage condition: OK to freeze, protect from light. color: yellow-white. solubility: DMSO: 100 . mg/mL. shipped in: ambient. storage temp.: 2-8°C. Storage Class Code: 11 - Combustible Solids. WGK: WGK 2. Flash Point(F): Not applicable. Flash Point(C): Not applicable.