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Chemical Compound Review

Prinomastat     (3R)-N-hydroxy-2,2-dimethyl- 4-(4-pyridin-4...

Synonyms: CHEMBL75094, AG-E-40511, AG-3354, AG-3362, AC1LAD25, ...
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Disease relevance of AG 3340

  • This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy [1].
  • The toxicities of prinomastat were arthralgia, stiffness, and joint swelling [1].
  • Treatment with Prinomastat did not affect formation of liver metastases (P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% (P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases [2].
  • Administration of Prinomastat significantly improved PDT-mediated tumor response (P = 0.02) without affecting normal skin photosensitization [3].
  • Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion [4].

Psychiatry related information on AG 3340

  • We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly predictable regional and systemic metastatic patterns [5].

High impact information on AG 3340

  • Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer [1].
  • The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections (P < 0.001), primarily due to the presence of smaller vessels (P = 0.004) [2].
  • Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035) [2].
  • Similarly, scid/nod mice receiving striatal implants of Tat-HAD-transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat-ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005) [6].
  • Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset [7].

Chemical compound and disease context of AG 3340


Biological context of AG 3340


Anatomical context of AG 3340

  • We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice [4].
  • PURPOSE: This randomized phase II, parallel-design study evaluated preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients with resectable adenocarcinoma of the esophagus that were stage II or greater [13].
  • At day 14 after intravitreal injection, levels of prinomastat in the vitreous and choroid were 1.4 ng/mg and 7.8 ng/mg, respectively [14].
  • RESULTS: In the rats treated with a relatively selective MMP-2 inhibitor, AG3340, the WM lesions after chronic cerebral hypoperfusion were significantly less severe, and the number of activated astroglia and microglia were also significantly lower as compared with the vehicle-treated rats [15].

Associations of AG 3340 with other chemical compounds

  • In contrast, long-term Prinomastat inhibition of MT1-MMP-dependent pro-alphav cleavage and thus alphavbeta3 integrin maturation strongly inhibited cell motility [10].
  • Eligible patients were randomized to preoperative prinomastat or placebo, plus continuous infusion 5-FU, cisplatin, paclitaxel, and concurrent radiotherapy [13].
  • Between these two enantiomers the eutomer (R)-b proved to be 24.7 times and 15.3 times more potent than CGS 27023A and the parent compound a on MMP-2, maintaining a higher index of MMP-2/MMP-1 selectivity compared with CGS 27023A and the more potent inhibitor Prinomastat [16].
  • The parameters thus obtained were used in order to study the docking of some known MMPi (Batimastat, CGS 27023A and Prinomastat) and our previously described inhibitor a which had shown an inhibitory activity for MMP-1, and -2, with the aim of explaining the different selectivity [16].

Gene context of AG 3340


Analytical, diagnostic and therapeutic context of AG 3340


  1. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. Bissett, D., O'Byrne, K.J., von Pawel, J., Gatzemeier, U., Price, A., Nicolson, M., Mercier, R., Mazabel, E., Penning, C., Zhang, M.H., Collier, M.A., Shepherd, F.A. J. Clin. Oncol. (2005) [Pubmed]
  2. Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Chantrain, C.F., Shimada, H., Jodele, S., Groshen, S., Ye, W., Shalinsky, D.R., Werb, Z., Coussens, L.M., DeClerck, Y.A. Cancer Res. (2004) [Pubmed]
  3. The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model. Ferrario, A., Chantrain, C.F., von Tiehl, K., Buckley, S., Rucker, N., Shalinsky, D.R., Shimada, H., DeClerck, Y.A., Gomer, C.J. Cancer Res. (2004) [Pubmed]
  4. Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. Price, A., Shi, Q., Morris, D., Wilcox, M.E., Brasher, P.M., Rewcastle, N.B., Shalinsky, D., Zou, H., Appelt, K., Johnston, R.N., Yong, V.W., Edwards, D., Forsyth, P. Clin. Cancer Res. (1999) [Pubmed]
  5. Early combined treatment with carboplatin and the MMP inhibitor, prinomastat, prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model. Liu, J., Tsao, M.S., Pagura, M., Shalinsky, D.R., Khoka, R., Fata, J., Johnston, M.R. Lung Cancer (2003) [Pubmed]
  6. HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Johnston, J.B., Zhang, K., Silva, C., Shalinsky, D.R., Conant, K., Ni, W., Corbett, D., Yong, V.W., Power, C. Ann. Neurol. (2001) [Pubmed]
  7. Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas. Savinov, A.Y., Rozanov, D.V., Golubkov, V.S., Wong, F.S., Strongin, A.Y. J. Biol. Chem. (2005) [Pubmed]
  8. Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer. Bonomi, P. Semin. Oncol. (2002) [Pubmed]
  9. Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor. Hande, K.R., Collier, M., Paradiso, L., Stuart-Smith, J., Dixon, M., Clendeninn, N., Yeun, G., Alberti, D., Binger, K., Wilding, G. Clin. Cancer Res. (2004) [Pubmed]
  10. Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells. Deryugina, E.I., Ratnikov, B.I., Strongin, A.Y. Int. J. Cancer (2003) [Pubmed]
  11. Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy. Behrendt, C.E., Ruiz, R.B. Thromb. Haemost. (2003) [Pubmed]
  12. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Shalinsky, D.R., Brekken, J., Zou, H., McDermott, C.D., Forsyth, P., Edwards, D., Margosiak, S., Bender, S., Truitt, G., Wood, A., Varki, N.M., Appelt, K. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
  13. Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma. Heath, E.I., Burtness, B.A., Kleinberg, L., Salem, R.R., Yang, S.C., Heitmiller, R.F., Canto, M.I., Knisely, J.P., Topazian, M., Montgomery, E., Tsottles, N., Pithavala, Y., Rohmiller, B., Collier, M., Forastiere, A.A. Investigational new drugs. (2006) [Pubmed]
  14. Evaluation of intraocular pharmacokinetics and toxicity of prinomastat (AG3340) in the rabbit. Cheng, L., Rivero, M.E., Garcia, C.R., McDermott, C.D., Keefe, K.S., Wiley, C.A., Soules, K.A., Bergeron-Lynn, G., Vekich, S., Zhang, K., Appelt, K., Freeman, W.R. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. (2001) [Pubmed]
  15. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Nakaji, K., Ihara, M., Takahashi, C., Itohara, S., Noda, M., Takahashi, R., Tomimoto, H. Stroke (2006) [Pubmed]
  16. Amber force field implementation, molecular modelling study, synthesis and MMP-1/MMP-2 inhibition profile of (R)- and (S)-N-hydroxy-2-(N-isopropoxybiphenyl-4-ylsulfonamido)-3-methylbutanamides. Tuccinardi, T., Martinelli, A., Nuti, E., Carelli, P., Balzano, F., Uccello-Barretta, G., Murphy, G., Rossello, A. Bioorg. Med. Chem. (2006) [Pubmed]
  17. Matrix metalloproteinase-2 and -9 expression increases in Mycoplasma-infected airways but is not required for microvascular remodeling. Baluk, P., Raymond, W.W., Ator, E., Coussens, L.M., McDonald, D.M., Caughey, G.H. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  18. Pharmacologic and Genetic Manipulation of MMP-2 and -9 Affects Retinal Neovascularization in Rodent Models of OIR. Barnett, J.M., McCollum, G.W., Fowler, J.A., Duan, J.J., Kay, J.D., Liu, R.Q., Bingaman, D.P., Penn, J.S. Invest. Ophthalmol. Vis. Sci. (2007) [Pubmed]
  19. Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340). Foda, H.D., Rollo, E.E., Drews, M., Conner, C., Appelt, K., Shalinsky, D.R., Zucker, S. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  20. Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations. Shalinsky, D.R., Brekken, J., Zou, H., Kolis, S., Wood, A., Webber, S., Appelt, K. Investigational new drugs. (1998) [Pubmed]
  21. Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors: single agent and combination chemotherapy studies. Shalinsky, D.R., Brekken, J., Zou, H., Bloom, L.A., McDermott, C.D., Zook, S., Varki, N.M., Appelt, K. Clin. Cancer Res. (1999) [Pubmed]
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