Description
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 (Ki = 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.
Biochem/physiol Actions
Primary Target
SHP2
Reversible: yes
Secondary Target
Other PTPs
Target IC₅₀: 5.5, 9.0 and 10.8 µ
Packaging
Packaged under inert gas
Preparation Note
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
Disclaimer
Toxicity: Standard Handling (A)
