{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:53:25Z","timestamp":1791309205333,"version":"4.3.1"},"reference-count":23,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2015,3,18]],"date-time":"2015-03-18T00:00:00Z","timestamp":1426636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the development and\/or progression of human diseases. Grx and Prx are overexpressed in human cancers, including human lung cancers. BNP7787 is a novel investigational agent that has been evaluated in previous clinical studies, including non-small cell lung cancer (NSCLC) studies. Herein, data from activity assays, mass spectrometry analyses, and X-ray crystallographic studies indicate that BNP7787 forms mixed disulfides with select cysteine residues on Grx and Prx and modulates their function. Studies of interactions between BNP7787 and Trx have been conducted and reported separately. Despite the fact that Trx, Grx, and Prx are functionally distinct proteins that impact oxidative stress, cell proliferation and disease processes through different intracellular pathways, BNP7787 can modify each protein and appears to modulate function through mechanisms that are unique to each target protein. Tumor cells are often genomically heterogeneous containing subpopulations of cancer cells that often express different tumor-promoting proteins or that have multiple dysregulated signaling pathways modulating cell proliferation and drug resistance. A multi-targeted agent that simultaneously modulates activity of proteins important in mediating cell proliferation  by functionally distinct intracellular pathways could have many potentially useful therapeutic applications.<\/jats:p>","DOI":"10.3390\/molecules20034928","type":"journal-article","created":{"date-parts":[[2015,3,18]],"date-time":"2015-03-18T14:09:08Z","timestamp":1426687748000},"page":"4928-4950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Cysteine Specific Targeting of the Functionally Distinct Peroxiredoxin and Glutaredoxin Proteins by the Investigational Disulfide BNP7787"],"prefix":"10.3390","volume":"20","author":[{"given":"Aulma","family":"Parker","sequence":"first","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavankumar","family":"Petluru","sequence":"additional","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki","family":"Nienaber","sequence":"additional","affiliation":[{"name":"Zenobia Therapeutics, Inc., 505 Coast Blvd. South, Suite 111, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Badger","sequence":"additional","affiliation":[{"name":"Zenobia Therapeutics, Inc., 505 Coast Blvd. South, Suite 111, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsy","family":"Leverett","sequence":"additional","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamwing","family":"Jair","sequence":"additional","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Sridhar","sequence":"additional","affiliation":[{"name":"Zenobia Therapeutics, Inc., 505 Coast Blvd. South, Suite 111, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheyenne","family":"Logan","sequence":"additional","affiliation":[{"name":"Zenobia Therapeutics, Inc., 505 Coast Blvd. South, Suite 111, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Ayala","sequence":"additional","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Kochat","sequence":"additional","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick","family":"Hausheer","sequence":"additional","affiliation":[{"name":"BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Ste. 1250, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1134\/S0006297908130099","article-title":"Involvement of thio-, peroxi-, and glutaredoxins in cell redox-dependent processes","volume":"73","author":"Kalinina","year":"2008","journal-title":"Biochemistry (Moscow)"},{"key":"ref_2","first-page":"1026","article-title":"BNP7787 forms novel covalent adducts on human thioredoxin and modulates thioredoxin activity","volume":"2","author":"Parker","year":"2014","journal-title":"J. Pharmacol. Clin. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13398","DOI":"10.1074\/jbc.275.18.13398","article-title":"Transcriptional regulation of glutaredoxin and thioredoxin pathways and related enzymes in response to oxidative stress","volume":"275","author":"Jurado","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1124\/jpet.300.1.142","article-title":"Inhibition of gamma-glutamyl transpeptidase or cysteine S-conjugate beta-lyase activity blocks the nephrotoxicity of cisplatin in mice","volume":"300","author":"Townsend","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30374","DOI":"10.1074\/jbc.M100020200","article-title":"Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2","volume":"276","author":"Gladyshev","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1073\/pnas.76.5.2158","article-title":"Glutathione-dependent hydrogen donor system for calf thymus ribonucleoside-diphosphate reductase","volume":"76","author":"Luthman","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.canep.2009.08.006","article-title":"Preferential overexpression of glutaredoxin3 in human colon and lung carcinoma","volume":"33","author":"Cha","year":"2009","journal-title":"Cancer Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13963","DOI":"10.1016\/S0021-9258(18)71625-6","article-title":"Thioredoxin and glutaredoxin systems","volume":"264","author":"Holmgren","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/ijc.20294","article-title":"Peroxiredoxins, a novel family in lung cancer","volume":"111","author":"Lehtonen","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7004","DOI":"10.1073\/pnas.1013012108","article-title":"Sulfiredoxin-peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling","volume":"108","author":"Wei","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1158\/1078-0432.CCR-07-4457","article-title":"Up-regulation of peroxiredoxin 1 in lung cancer and its implication as a prognostic and therapeutic target","volume":"14","author":"Kim","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0968-0004(02)00003-8","article-title":"Structure, mechanism and regulation of peroxiredoxins","volume":"28","author":"Wood","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1365-2559.2009.03381.x","article-title":"Expression profiles of thioredoxin family proteins in lung cancer tissue: Correlation with proliferation and differentiation","volume":"55","author":"Fernandes","year":"2009","journal-title":"Histopathology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/j.1440-1843.2006.00849.x","article-title":"Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung","volume":"11","author":"Park","year":"2006","journal-title":"Respirology"},{"key":"ref_15","first-page":"7","article-title":"Comprehensive meta-analysis of survival outcomes from two randomized multicenter trials in first-line advanced non-small cell lung cancer in patients treated with the novel investigational antitumor-enhancing and chemoprotective agent tavocept","volume":"2","author":"Hausheer","year":"2009","journal-title":"Eur. J. Clin. Med. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0009-9236(03)00150-4","article-title":"Pharmacokinetics and preliminary clinical data of the novel chemoprotectant BNP7787 and cisplatin and their metabolites","volume":"74","author":"Verschraagen","year":"2003","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6075","DOI":"10.1016\/S0040-4039(00)98032-8","article-title":"Synthesis of asymmetric disulfides with thiol sulfonates immobilized on a polystyrene support","volume":"31","author":"Rajca","year":"1999","journal-title":"Tetrahedron Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/1046-5928(91)90085-W","article-title":"Characterization of homogeneous recombinant glutaredoxin from Escherichia coli: Purification from an inducible lambda PL expression system and properties of a novel elongated form","volume":"2","author":"Bjornberg","year":"1991","journal-title":"Protein Expr. Purif."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0076-6879(99)00128-7","article-title":"Isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin","volume":"300","author":"Chae","year":"1999","journal-title":"Methods Enzymol."},{"key":"ref_20","unstructured":"MIFit Open Source Project. Available online:http:\/\/code.google.com\/p\/mifit\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1107\/S0907444996012255","article-title":"Refinement of macromolecular structures by the maximum-likelihood method","volume":"53","author":"Murshudov","year":"1997","journal-title":"Acta Crystallogr. D Biol. Chrystallogr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.cell.2009.08.017","article-title":"Heterogeneity in cancer: Cancer stem cells versus clonal evolution","volume":"138","author":"Shackleton","year":"2009","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/20\/3\/4928\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:43:40Z","timestamp":1760215420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/20\/3\/4928"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,18]]},"references-count":23,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,3]]}},"alternative-id":["molecules20034928"],"URL":"https:\/\/doi.org\/10.3390\/molecules20034928","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,18]]}}}