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O-5679 OSU-03012, Hydrochloride Salt, >98%

[OSU03012]

M.W. 496.91

C26H19F3N4O•HCl

[742112-33-0]

Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO.  Disposal:  A

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• Inhibitor of phosphoinositide-dependent kinase-1.  OSU-03012 inhibited both recombinant 3-phosphoinositide-dependent kinase-1 activity and PC-3 cell viability with similar IC50 values of ~5 µM.  Exposure of PC-3 cells to OSU-03012 led to Akt dephosphorylation and suppression of p70 S6 kinase activity.  Moreover, overexpression of PDK-1 and Akt partially protected against OSU-03012-induced apoptosis.  Screening in a panel of 60 cell lines and testing in PC-3 cells indicated that the mean concentration for total growth inhibition by OSU-03012 was about 3 µM.  Zhu, J., et al.  "From the Cyclooxygenase-2 Inhibitor Celecoxib to a Novel Class of 3-Phosphoinositide-Dependent Protein Kinase-1 Inhibitors."  Cancer Res. 64:  4309-4318 (2004).

• OSU-03012 showed no increased resistance in the mutant cells Ba/F3p210E255K and Ba/F3p210T315I, with an IC50 of 5 µM irrespective of mutations.  Nevertheless, the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced in the presence of OSU-03012.  OSU-03012 appears to hold promise for overcoming imatinib mesylate resistance, especially with the Abl mutant T315I.  Tseng P.H., et al.  "Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance."  Blood 105:  4021-4027 (2005).

• The dose of OSU-03012 to induce 50% chronic lymphocytic leukemia cell death (LC50) at 24 hours was 7.1 µM.  Additionally, OSU-03012 induces apoptosis by activation of the intrinsic, mitochondrial pathway of apoptosis but also triggers cell death pathways which are caspase independent.  Johnson A.J., et al.  "A novel celecoxib derivative, OSU-03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- and Bcl-2-independent mechanism."  Blood 105:  2504-2509 (2005).

• OSU-03012 blocked phosphorylated Akt (P-Akt) and its downstream signalling through 4E binding protein and glycogen synthase kinase at concentrations well below that of celecoxib.  Disruption of P-Akt resulted in apoptosis and more than 90% cell death.  Kucab J.E., et al.  "Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours."  Breast Cancer Res. 7:  R796-R807 (2005).

• OSU-03012 caused cell death in a dose-dependent manner that was not affected by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function.  OSU-03012 induces glioma cell death that depends on lysosomal dysfunction, endoplasmic reticulum stress, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by inhibition of protective signaling pathways or by irradiation.  Yacoub A., et al.  "OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells."  Mol. Pharmacol. 70:  589-603 (2006).

• Sold for laboratory or manufacturing purposes only; not for human, veterinary, food, or household use.

• This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.

• Not available in some countries; not available to some institutions; not available for some uses.