Elesclomol Explained

Elesclomol (INN, codenamed STA-4783) is a drug that triggers apoptosis (programmed cell death) in cancer cells. It is being developed by Synta Pharmaceuticals and GlaxoSmithKline as a chemotherapy adjuvant, and has received both fast track and orphan drug status from the U.S. Food and Drug Administration for the treatment of metastatic melanoma.[1] Synta Pharmaceuticals announced on February 26, 2009 the suspension of all clinical trials involving Elesclomol due to safety concerns.[2] In March 2010, Synta announced that the FDA had approved resuming clinical development of elesclomol, and that they expected to initiate one or more clinical trials for elesclomol in the second half of the year.[3]

In a small, randomized phase II study, elesclomol was shown to significantly increase progression-free survival in people with metastatic melanoma when given in addition to paclitaxel (Taxol).[4] [5]

Results from a phase III trial were announced in March 2013. The study was halted when it was determined that addition of elesclomol to paclitaxel didn't significantly increase progression-free survival.[6]

Studies in preclinical models suggested that Elesclomol may be effective in Ewing sarcoma cells with elevated levels of cellular oxidative stress.[7]

Mechanism of action

Elesclomol induces oxidative stress by provoking a buildup of reactive oxygen species within cancer cells.[8] Elesclomol requires a redox active metal ion to function. The Cu(II) complex is 34 times more potent than the Ni(II) complex and 1040-fold more potent than the Pt(II) complex.[9]

Discovery

Elesclomol was first synthesized at Shinogi BioResearch in Lexington, MA. Its efficacy against cancer was discovered by scientists at Shionogi BioResearch. “It was pure chemist’s joy,” Synta's Chen said. “Homemade, random, and clearly made for no particular purpose. It was the only one that worked on everything we tried.”[10]

Notes and References

  1. Synta And GlaxoSmithKline Announce Elesclomol Granted Orphan Drug Designation By The FDA . January 30, 2008 . Medical News Today . November 30, 2008 . December 8, 2008 . https://web.archive.org/web/20081208041029/http://www.medicalnewstoday.com/articles/95590.php . dead . Retrieved November 30, 2008.
  2. Web site: Synta Pharmaceuticals press release . https://archive.today/20120712134533/http://ir.syntapharma.com/phoenix.zhtml?c=147988&p=irol-newsArticle&ID=1260685&highlight= . dead . July 12, 2012 . February 26, 2009 .
  3. Web site: Synta Announces Elesclomol Clinical Development to Resume . March 2, 2010 .
  4. Web site: Prous Science Molecule of the Month: Elesclomol . December 2007 . . dead . https://web.archive.org/web/20080220080357/http://www.prous.com/molecules/default.asp?ID=166 . 2008-02-20 . Retrieved November 30, 2008.
  5. Qu Y, Wang J, Sim MS, Liu B, Giuliano A, Barsoum J, Cui X . 1312270 . Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells . Breast Cancer Research and Treatment . 121 . 2 . 311–21 . June 2010 . 19609669 . 10.1007/s10549-009-0470-6 .
  6. O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A . 6 . Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma . Journal of Clinical Oncology . 31 . 9 . 1211–8 . March 2013 . 23401447 . 10.1200/JCO.2012.44.5585 . free .
  7. Marchetto A, Ohmura S, Orth MF, Knott MM, Colombo MV, Arrigoni C, Bardinet V, Saucier D, Wehweck FS, Li J, Stein S, Gerke JS, Baldauf MC, Musa J, Dallmayer M, Romero-Pérez L, Hölting TL, Amatruda JF, Cossarizza A, Henssen AG, Kirchner T, Moretti M, Cidre-Aranaz F, Sannino G, Grünewald TG . 6 . Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma . Nature Communications . 11 . 1 . 2423 . May 2020 . 32415069 . 7228971 . 10.1038/s41467-020-16244-2 . 2020NatCo..11.2423M .
  8. Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang CY, Zhang M, Du Z, Barsoum J, Bertin J . 6 . Elesclomol induces cancer cell apoptosis through oxidative stress . Molecular Cancer Therapeutics . 7 . 8 . 2319–27 . August 2008 . 18723479 . 10.1158/1535-7163.MCT-08-0298 . free .
  9. Yadav AA, Patel D, Wu X, Hasinoff BB . Molecular mechanisms of the biological activity of the anticancer drug elesclomol and its complexes with Cu(II), Ni(II) and Pt(II) . Journal of Inorganic Biochemistry . 126 . 1–6 . September 2013 . 23707906 . 10.1016/j.jinorgbio.2013.04.013 . 20624982 .
  10. The Treatment - Why is it so difficult to develop drugs for cancer? . Gladwell M . 17 May 2010 . . 13 September 2014 .

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