PIP3 Antagonist II, DM-PIT-1

A cell-permeable benzoylthiourea compound that is shown to compete against PIP3 (Cat. No. 524615) for binding PH (pleckstrin-homology) domains of Akt1 (IC₅₀ ≥31 µM using recombinant human Akt1 aa 1-123), ARNO, GRP1, and PKD1, while lacking activity against PIP3 Btk PH domain ineraction, PI-4,5-P2 (Cat. Nos. 524614, 524644, and 524646) PLC-δ PH domain binding, or PI-3,4-P2 TAPP1/2 PH domains binding, resulting in effective blockage of PIP3-dependent PI3K-PDK1-Akt signaling pathway activation in human glioblastoma U87MG cultures (25 to 100 µM for 3 d) and (5 min 100 ng/ml) PDGF-induced Akt and GRP membrane translocation (by 85% and 70%, respectively, with 1 h 100 µM pretreatment) in serum-starved human breast cancer SUM159 cells, while being inactive against PDGF-induced Btk translocation or (5 min 250 ng/ml) PMA-induced PLC-δ and TAPP1/2 translocations. Although DM-PIT-1 can be administered as a DMSO stock for effective culture treatments, incorporating DM-PIT-1 into PEG-PE mixed micelles is reported to enhance its solubility (up to 1 mM), and presumably delivery efficiency (57% vs. 67% U87MG viability after 24 h 50 µM drug treatment, respectively, with or without PEG-PE encapsulation), making large dosage delivery possible for more effective in vivo administrations (5% vs. 41% of control 4T1 tumor size in mice after 8 daily i.v. dosages of 1 mg/kg micelles-formulated or 0.4 mg/kg free drug, respectively).

A cell-permeable benzoylthiourea compound that is shown to compete against PIP3 (Cat. No. 524615) for binding PH domains of Akt1 (IC₅₀ ≥31 µM), ARNO, GRP1, and PKD1. Effectively blocks PIP3-dependent cellular PI3K-PDK1-Akt signaling pathway activation in U87MG (25 to 100 µM for 3 d) and PDGF-induced Akt and GRP membrane translocation in serum-starved SUM159 cells (1 h 100 µM pretreatment), while being inactive against PDGF-induced Btk translocation or PMA-induced PLC-δ and TAPP1/2 translocations. Although DM-PIT-1 can be administered as a DMSO stock for effective culture treatments, incorporating DM-PIT-1 into PEG-PE mixed micelles enhances its solubility (up to 1 mM) and i.v. dosing limit for more effective in vivo administrations (5% vs. 41% of control 4T1 tumor size in mice via 1 mg/kg micelles-formulated or 0.4 mg/kg free drug daily i.v., respectively).

Packaged under inert gas

Toxicity: Regulatory Review (Z)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Miao, B., et al. 2010. Proc. Natl. Acad. Sci. USA107, 20126.
Skidan, I., et al. 2009. Drug Deliv.16, 45.

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