OSU-03012
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MedKoo CAT#: 200272

CAS#: 742112-33-0 (free base)

Description: OSU03012; also known as AR12, is an orally available, targeted anti-cancer agent that has been shown in pre-clinical studies to inhibit PDK-1, a protein in the PI3K/Akt pathway that is involved in the growth and proliferation of cells, including cancer cells. AR-12 may also cause cell death through the induction of stress in the endoplasmic reticulum. We are currently conducting a multi-centered Phase I clinical study of AR-12 in adult patients with advanced or recurrent solid tumors or lymphoma.


Chemical Structure

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OSU-03012
CAS# 742112-33-0 (free base)

Theoretical Analysis

MedKoo Cat#: 200272
Name: OSU-03012
CAS#: 742112-33-0 (free base)
Chemical Formula: C26H19F3N4O
Exact Mass: 460.1511
Molecular Weight: 460.45
Elemental Analysis: C, 67.82; H, 4.16; F, 12.38; N, 12.17; O, 3.47

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 850.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2450.0 Ready to ship
2.0g USD 4450.0 Ready to ship
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Related CAS #: 742112-33-0 (free base)   1471979-81-3 (HCl)    

Synonym: AR12; AR-12; AR 12; OSU03012; OSU-03012; OSU 03012.

IUPAC/Chemical Name: 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide

InChi Key: YULUCECVQOCQFQ-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H19F3N4O/c27-26(28,29)24-14-23(33(32-24)20-10-8-19(9-11-20)31-25(34)15-30)18-7-12-22-17(13-18)6-5-16-3-1-2-4-21(16)22/h1-14H,15,30H2,(H,31,34)

SMILES Code: O=C(NC1=CC=C(N2N=C(C(F)(F)F)C=C2C3=CC=C4C5=CC=CC=C5C=CC4=C3)C=C1)CN

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: soluble in DMSO, not soluble in water.

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: OSU-03012 (AR-12) is an inhibitor of recombinant PDK-1(phosphoinositide-dependent kinase 1) with IC50 of 5 μM.
In vitro activity: Vero cells were treated with AR12 (1 μM; 2 μM) and then infected with SARS-CoV-2 at 0.01 and 0.001 multiplicities of infection (MOI). Twenty-four and forty-eight hours after infection, cells were fixed in place and permeabilized, and stained for expression of the SARS-CoV-2 spike protein, total GRP78 and total ERK2 as a loading control. In a dose-dependent fashion, AR12 suppressed the production of virus spike protein (Fig. 2 A and B). Cells were then infected and treated with AR12 (2 μM) 3 h, 6 h and 12 h after infection, with cells being fixed and stained 24 h after infection. Treatment of infected cells with AR12 significantly reduced the amount of spike protein produced in the infected cells as well as the amount of GRP78 in the cells (Fig. 2C and D). Reference: Biochem Pharmacol. 2020 Dec; 182: 114227. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502229/
In vivo activity: To study the effects of OSU-03012 on tumor progression in vivo, this study treated the Ishikawa xenograft with OSU-03012. First of all, compared with the control group, the tumor volume of mice in the OSU-03012 treatment group was significantly reduced (Figure 6A and B).The results showed that the mass and volume of the tumor were significantly reduced with OSU-03012 treatment (0.222 ± 0.07235g, 339.6 ± 103.2 mm3, n=5) relative to the vehicle controls (0.624 ± 0.02694 g, 1170 ± 84.51 mm3, n=5, Figure 6C and E); meanwhile, the body weights of the mice remained consistent throughout the duration of the experiment, exhibiting no serious toxicity at specified dose regimens (Figure 6D). These results demonstrate that oral administration of OSU-03012 can prevent EC progression. Reference: Drug Des Devel Ther. 2021; 15: 1797–1810. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096345/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 65.2

Preparing Stock Solutions

The following data is based on the product molecular weight 460.45 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Rayner JO, Roberts RA, Kim J, Poklepovic A, Roberts JL, Booth L, Dent P. AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication. Biochem Pharmacol. 2020 Dec;182:114227. doi: 10.1016/j.bcp.2020.114227. Epub 2020 Sep 20. PMID: 32966814; PMCID: PMC7502229. 2. Zhang S, Zou Y, Guo Q, Chen J, Xu L, Wan X, Zhang Z, Li B, Chu H. AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus. Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00236-20. doi: 10.1128/AAC.00236-20. PMID: 32482678; PMCID: PMC7526805. 3. Ding L, Ren C, Yang L, Wu Z, Li F, Jiang D, Zhu Y, Lu J. OSU-03012 Disrupts Akt Signaling and Prevents Endometrial Carcinoma Progression in vitro and in vivo. Drug Des Devel Ther. 2021 Apr 30;15:1797-1810. doi: 10.2147/DDDT.S304128. PMID: 33958857; PMCID: PMC8096345. 4. Chan JF, Zhu Z, Chu H, Yuan S, Chik KK, Chan CC, Poon VK, Yip CC, Zhang X, Tsang JO, Zou Z, Tee KM, Shuai H, Lu G, Yuen KY. The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy. Antiviral Res. 2018 Dec;160:38-47. doi: 10.1016/j.antiviral.2018.10.007. Epub 2018 Oct 13. PMID: 30326204; PMCID: PMC7113887.
In vitro protocol: 1. Rayner JO, Roberts RA, Kim J, Poklepovic A, Roberts JL, Booth L, Dent P. AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication. Biochem Pharmacol. 2020 Dec;182:114227. doi: 10.1016/j.bcp.2020.114227. Epub 2020 Sep 20. PMID: 32966814; PMCID: PMC7502229. 2. Zhang S, Zou Y, Guo Q, Chen J, Xu L, Wan X, Zhang Z, Li B, Chu H. AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus. Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00236-20. doi: 10.1128/AAC.00236-20. PMID: 32482678; PMCID: PMC7526805.
In vivo protocol: 1. Ding L, Ren C, Yang L, Wu Z, Li F, Jiang D, Zhu Y, Lu J. OSU-03012 Disrupts Akt Signaling and Prevents Endometrial Carcinoma Progression in vitro and in vivo. Drug Des Devel Ther. 2021 Apr 30;15:1797-1810. doi: 10.2147/DDDT.S304128. PMID: 33958857; PMCID: PMC8096345. 2. Chan JF, Zhu Z, Chu H, Yuan S, Chik KK, Chan CC, Poon VK, Yip CC, Zhang X, Tsang JO, Zou Z, Tee KM, Shuai H, Lu G, Yuen KY. The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy. Antiviral Res. 2018 Dec;160:38-47. doi: 10.1016/j.antiviral.2018.10.007. Epub 2018 Oct 13. PMID: 30326204; PMCID: PMC7113887.

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1: Kuo WW, Weng JR, Huang CY, Tsai CH, Liu WH, Wen CH, Tsai SC, Wu CH. Exploring the molecular mechanisms of OSU-03012 on vascular smooth muscle cell proliferation. Mol Cell Biochem. 2010 Jul 13. [Epub ahead of print] PubMed PMID: 20625798.

2: Hamed HA, Yacoub A, Park MA, Eulitt P, Sarkar D, Dimitriev IP, Chen CS, Grant S, Curiel DT, Fisher PB, Dent P. OSU-03012 enhances Ad.mda-7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins. Cancer Biol Ther. 2010 Apr 4;9(7). [Epub ahead of print] PubMed PMID: 20107314; PubMed Central PMCID: PMC2888700.

3: Bai LY, Weng JR, Tsai CH, Sargeant A, Lin CW, Chiu CF. OSU-03012 sensitizes TIB-196 myeloma cells to imatinib mesylate via AMP-activated protein kinase and STAT3 pathways. Leuk Res. 2010 Jun;34(6):816-20. Epub 2009 Dec 14. PubMed PMID: 20006997.

4: Chiu HC, Soni S, Kulp SK, Curry H, Wang D, Gunn JS, Schlesinger LS, Chen CS. Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent. J Biomed Sci. 2009 Dec 9;16:110. PubMed PMID: 20003180; PubMed Central PMCID: PMC2801672.

5: Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 2009 Aug;46(8):497-510. Epub 2009 Jun 7. Review. PubMed PMID: 19505876.

6: Lee TX, 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. Epub 2009 Apr 7. PubMed PMID: 19359162; PubMed Central PMCID: PMC2692816.

7: Gao M, Yeh PY, Lu YS, Hsu CH, Chen KF, Lee WC, Feng WC, Chen CS, Kuo ML, Cheng AL. OSU-03012, a novel celecoxib derivative, induces reactive oxygen species-related autophagy in hepatocellular carcinoma. Cancer Res. 2008 Nov 15;68(22):9348-57. PubMed PMID: 19010909.

8: Ding H, Han C, Guo D, Wang D, Duan W, Chen CS, D'Ambrosio SM. Sensitivity to the non-COX inhibiting celecoxib derivative, OSU03012, is p21(WAF1/CIP1) dependent. Int J Cancer. 2008 Dec 15;123(12):2931-8. PubMed PMID: 18798266; PubMed Central PMCID: PMC2605165.

9: Ding H, Han C, Guo D, Wang D, Chen CS, D'Ambrosio SM. OSU03012 activates Erk1/2 and Cdks leading to the accumulation of cells in the S-phase and apoptosis. Int J Cancer. 2008 Dec 15;123(12):2923-30. PubMed PMID: 18798257.

10: Weng SC, Kashida Y, Kulp SK, Wang D, Brueggemeier RW, Shapiro CL, Chen CS. Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor. Mol Cancer Ther. 2008 Apr;7(4):800-8. PubMed PMID: 18413793.



Additional Information

Related:
742112-33-0(AR-12)
1471979-81-3 (AR-12 Hydrochloride)

AR-12 (formerly known as OSU-03012) is a potentially first-in-class, orally available, targeted anti-cancer agent that inhibits PDK-1, a protein in the PI3K/Akt pathway, and also causes cell death through the induction of endoplasmic reticulum (ER) stress. Arno is currently enrolling patients with advanced or recurrent solid tumors or lymphoma in a Phase I clinical study. Preclinical data have demonstrated that AR-12 has activity in a wide range of tumor types and sas both a single agent and in combination with several widely used anti-cancer agents including Avastin®, Herceptin®, Gleevec®, Tarceva®, Sorafinib®, Nexavar®, and tamoxifen.
 
OSU-03012 is a derivative of celecoxib with anticancer activity. The mechanism of action is presumably 3-phosphoinositide-dependent kinase 1 (PDK1) inhibition.  OSU-03012 inhibited cell growth of Huh7, Hep3B, and HepG2 cells with IC(50) below 1 mumol/L. In Huh7 cells, OSU-03012 did not suppress PDK1 or AKT activity. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and flow cytometry analysis indicated that OSU-03012 did not induce cellular apoptosis. Instead, morphologic studies by light and electron microscopy, as well as special biological staining with monodansylcadaverine, acridine orange, and microtubule-associated protein 1 light chain 3, revealed OSU-03012-induced autophagy of Huh7 cells. This OSU-03012-induced autophagy was inhibited by 3-methyladenine. Moreover, reactive oxygen species (ROS) accumulation was detected after OSU-03012 treatment. Blocking ROS accumulation with ROS scavengers inhibited autophagy formation, indicating that ROS accumulation and subsequent autophagy formation might be a major mechanism of action of OSU-03012. Daily oral treatment of BALB/c nude mice with OSU-03012 suppressed the growth of Huh7 tumor xenografts. Electron microscopic observation indicated that OSU-03012 induced autophagy in vivo. Together, our results show that OSU-03012 induces autophagic cell death but not apoptosis in HCC and that the autophagy-inducing activity is at least partially related to ROS accumulation.( source: Cancer Res. 2008 Nov 15;68(22):9348-57., or http://www.ncbi.nlm.nih.gov/pubmed/19010909).