OSU-03012

Last updated
OSU-03012
OSU-03012.svg
Names
IUPAC name
2-Amino-N-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide
Other names
AR-12
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • 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)
    Key: YULUCECVQOCQFQ-UHFFFAOYSA-N
  • InChI=1/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)
    Key: YULUCECVQOCQFQ-UHFFFAOYAU
  • C1=CC=C2C(=C1)C=CC3=C2C=CC(=C3)C4=CC(=NN4C5=CC=C(C=C5)NC(=O)CN)C(F)(F)F
Properties
C26H19F3N4O
Molar mass 460.460 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

OSU-03012 (AR-12) is a celecoxib derivative with anticancer and anti-microbial activity. Unlike celecoxib, OSU-03012 does not inhibit COX, but inhibits several other important enzymes instead which may be useful in the treatment of some forms of cancer, [1] [2] When combined with PDE5 inhibitors such as sildenafil or tadalafil, OSU-03012 was found to show enhanced anti-tumour effects in cell culture. [3]

Contents

Antimicrobial agent

Antimicrobial activity is often not against the microbe directly (like conventional antibiotics), but rather host-directed activity that works on the cellular host to disrupt the pathogen within the cell. [16] Since the median lethal dose (LD50), in vitro , against macrophages is ~7 μM and near its effective concentration (EC50) [17] [18] formulation of the compound has been shown to enhances its activity. For example, encapsulation of OSU-03012 into biodegradable polymeric (Acetalated dextran) micro/nanoparticles significantly reduces cytotoxicity, increases drug concentration per a cell, reduces toxicity in vivo , and facilitates needle-free delivery in vivo . [19] [20]

Orphan drug designation

The European Commission has designated OSU-03012 as an orphan drug for use in combination with other drugs for treatment of two infections diseases, cryptococcosis and tularaemia. OSU-03012 received an orphan drug designation in combination with the antifungal drug fluconazole for cryptococcosis of the brain. It also received this designation for tularaemia in combination with the antibacterial drug gentamicin. [21]

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Kristy M. Ainslie is a Fred Eshelman Distinguished Professor in pharmaceutical science at University of North Carolina at Chapel Hill in the Eshelman School of Pharmacy and chair of the Division of Pharmacoengineering and Molecular Pharmaceutics. She is also joint in the UNC School of Medicine Department of Microbiology and Immunology and affiliated faculty in the UNC/NC State joint Biomedical Engineering department. Additionally, she is part of UNC's Biological and Biomedical Sciences Program (BBSP).

Karen Joy Shaw is an American microbiologist and discoverer of novel antifungal and antibacterial compounds. She is best known for her work on aminoglycoside resistance in bacteria as well as leading drug discovery research teams. As Senior Vice President of Biology at Trius Therapeutics, Inc. her work was critical to the development of the oxazolidinone antibiotic tedizolid phosphate (Sivextro) as well as the discovery of the TriBE inhibitors, a novel class of DNA gyrase/Topoisomerase IV antibacterial agents that target both Gram-positive and Gram-negative organisms.[2] As Chief Scientific Officer at Amplyx Pharmaceuticals, Shaw was responsible for the preclinical development of the novel antifungal fosmanogepix, a first-in-class broad-spectrum antifungal prodrug that is currently in Phase 2 clinical development for the treatment of invasive fungal infections. She also discovered APX2039, a unique Gwt1 inhibitor that is in preclinical development for the treatment of cryptococcal meningitis.

References

  1. ↑ Booth, L; Cruickshanks, N; Ridder, T; Chen, CS; Grant, S; Dent, P (Dec 2012). "OSU-03012 interacts with lapatinib to kill brain cancer cells". Cancer Biology and Therapy. 13 (14): 1501–11. doi:10.4161/cbt.22275. PMC   3542242 . PMID   22990204.
  2. ↑ Ma, Y; McCarty, SK; Kapuriya, NP; Brendel, VJ; Wang, C; Zhang, X; Jarjoura, D; Saji, M; Chen, CS; Ringel, MD (Aug 2013). "Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration". Journal of Clinical Endocrinology and Metabolism. 98 (8): E1314–22. doi:10.1210/jc.2012-3937. PMC   3733855 . PMID   23709653.
  3. ↑ Booth, L; Roberts, JL; Cruickshanks, N; Grant, S; Poklepovic, A; Dent, P (Oct 2014). "Regulation of OSU-03012 toxicity by ER stress proteins and ER stress-inducing drugs". Molecular Cancer Therapeutics. 13 (10): 2384–98. doi:10.1158/1535-7163.MCT-14-0172. PMC   4185238 . PMID   25103559. (This paper currently has an expression of concern, see doi:10.1158/1535-7163.MCT-19-0666 . If this is an intentional citation to a such a paper, please replace {{ expression of concern |...}} with {{ expression of concern |...|intentional=yes}}.)
  4. ↑ Liu, J; Qin, CK; Lv, W; Zhao, Q; Qin, CY (2013). "OSU-03012, a non-Cox inhibiting celecoxib derivative, induces apoptosis of human esophageal carcinoma cells through a p53/Bax/cytochrome c/caspase-9-dependent pathway" (PDF). Anticancer Drugs. 24 (7): 690–8. doi:10.1097/CAD.0b013e328362469f. PMID   23652278. S2CID   6028415. Archived from the original (PDF) on 2019-03-08.
  5. ↑ Koselny, K; Green, J; Favazzo, L; Glazier, VE; DiDone, L; Ransford, S; Krysan, DJ (8 Apr 2016). "Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase". ACS Infect Dis. 2 (4): 268–280. doi:10.1021/acsinfecdis.5b00134. PMC   4828684 . PMID   27088128.
  6. ↑ Koselny, K; Green, J; DiDone, L; Halterman, JP; Fothergill, AW; Wiederhold, NP; Patterson, TF; Cushion, MT; Rappelye, C; Wellington, M; Krysan, DJ (2016). "The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis". Antimicrob Agents Chemother. 60 (12): 7115–7127. doi:10.1128/AAC.01061-16. PMC   5118990 . PMID   27645246.
  7. ↑ Koselny, K; Green, J; DiDone, L; Halterman, JP; Fothergill, AW; Wiederhold, NP; Patterson, TF; Cushion, MT; Rappelye, C; Wellington, M; Krysan, DJ (2016). "The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis". Antimicrob Agents Chemother. 60 (12): 7115–7127. doi:10.1128/AAC.01061-16. PMC   5118990 . PMID   27645246.
  8. ↑ Collier, MA; Peine, KJ; Gautum, S; Oghumu, S; Varikuti, S; Borteh, H; Papenfuss, TL; Satoskar, AR; Bachelder, EM; Ainslie, KM (Feb 29, 2016). "Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles". International Journal of Pharmaceutics. 499 (1–2): 186–94. doi:10.1016/j.ijpharm.2016.01.004. PMC   5730989 . PMID   26768723.
  9. ↑ Ainslie; et al. "COMPOSITIONS AND METHODS FOR INHIBITING LEISHMANIA". Free Patents Online.
  10. ↑ Chiu, HC; Kulp, SK; Soni, S; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrob Agents Chemother. 53 (12): 5236–5244. doi:10.1128/aac.00555-09. PMC   2786354 . PMID   19805568.
  11. ↑ Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334–343. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  12. ↑ Chiu, HC; Soni, S; Kulp, SK; Curry, H; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent". J Biomed Sci. 16 (1): 110. doi: 10.1186/1423-0127-16-110 . PMC   2801672 . PMID   20003180.
  13. ↑ Hoang, KV; Curry, H; Collier, MA; Borteh, H; Bachelder, EM; Schlesinger, LS; Gunn, JS; Ainslie, KM (Mar 25, 2016). "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrob Agents Chemother. 60 (4): 2052–62. doi:10.1128/AAC.02228-15. PMC   4808193 . PMID   26787696.
  14. ↑ Lo, JH; Kulp, SK; Chen, CS; Chiu, HC (Dec 2014). "Sensitization of intracellular Salmonella enterica serovar Typhimurium to aminoglycosides in vitro and in vivo by a host-targeted antimicrobial agent". Antimicrob Agents Chemother. 58 (12): 7375–82. doi:10.1128/AAC.03778-14. PMC   4249550 . PMID   25267669.
  15. ↑ Dent, Paul; et al. (2014). "GRP78 / BiP / HSPA5 / Dna K is a universal therapeutic target for human disease". Journal of Cellular Physiology. 230 (7): 1661–1676. doi:10.1002/jcp.24919. PMC   4402027 . PMID   25546329.
  16. ↑ Collier, MA; Gallovic, MD; Peine, KJ; Duong, AD; Bachelder, EM; Gunn, JS; Schlesingr, LS; Ainslie, KM (Nov 2013). "Delivery of host cell-directed therapeutics for intracellular pathogen clearance". Expert Rev Anti Infect Ther. 11 (11): 1225–1235. doi:10.1586/14787210.2013.845524. PMC   4070714 . PMID   24134600.
  17. ↑ Chiu, HC; Kulp, SK; Soni, S; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrob Agents Chemother. 53 (12): 5236–5244. doi:10.1128/aac.00555-09. PMC   2786354 . PMID   19805568.
  18. ↑ Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334–343. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  19. ↑ Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334–343. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  20. ↑ Hoang, KV; Curry, H; Collier, MA; Borteh, H; Bachelder, EM; Schlesinger, LS; Gunn, JS; Ainslie, KM (Mar 25, 2016). "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrob Agents Chemother. 60 (4): 2052–62. doi:10.1128/AAC.02228-15. PMC   4808193 . PMID   26787696.
  21. ↑ Arno Therapeutics Inc receives European orphan drug designation for OSU-03012 to treat two infectious diseases. Reuters, 30 Apr 2015.
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