742112-33-0

Cyclooxygenase-2 (COX-2) appears to play a significant role in the development and progression of cancer and COX-2 inhibitors such as celecoxib exhibit anti-cancer activity. OSU03012 is an analog of celecoxib that exhibits anti-cancer activity in a COX-2-independent manner via inhibition of the phosphatidyl inositol-3-kinase/Akt pathway. It has an IC₅₀ value of 5 μM for inhibition of 3-phosphoinositide-dependent kinase-1, and therefore Akt activation, with no measurable COX-2 inhibition up to 50 μM. OSU03012 is a potent inhibitor of tumor cell growth with an average inhibitory concentration of 1.1 μM across a panel of 60 cancer cell lines. It does not inhibit signal transduction through the mitogen-activated protein kinase (MAPK) pathway. OSU03012 induces apoptosis of chronic lymphocytic leukemia cells independent of bcl-2 overexpression using both caspase-dependent and independent pathways.

OSU 03012 is a PDK1 inhibitor and inducer of caspase and p53-independent apoptosis, also used in the development of anticancer agents by modification of novel immunosuppressant FTY720 and PDK1 inhibitor OSU-03012, compound for treating Alzheimers diseases.

ChEBI: A member of the class of pyrazoles that is N-[4-(pyrazol-1-yl)phenyl]glycinamide in which the pyrazole ring is substituted at positions 3 and 5 by trifluoromethyl and phenanthrene-2-yl groups respectively.

This PDK1 inhibitor (FW = 460.45 g/mol; CAS 742112-33-0; Soluble to 100 mM in DMSO), systematically named 2-Amino-N-[4-[5- (2- phenanthrenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]phenyl]acetamide, blocks Akt signaling by targeting 3-Phosphoinositide-Dependent Protein Kinase-1 (IC50 = 2-3 μM). Exposure of PC-3 cells to this agent leads to Akt dephosphorylation and inhibition of p70 S6 kinase activity. OSU- 03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways. OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner When tested in vivo, OSU03012 inhibits the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779.

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[1] zhu j1, huang jw, tseng ph, yang yt, fowble j, shiau cw, shaw yj, kulp sk, chen cs. from the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. cancer res. 2004 jun 15;64(12):4309-18.
[2] lee tx1, packer md, huang j, akhmametyeva em, kulp sk, chen cs, giovannini m, jacob a, welling db, chang ls. growth inhibitory and anti-tumour activities of osu-03012, a novel pdk-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. eur j cancer. 2009 jun;45(9):1709-20.