A tacrolimus-related immunosuppressant with biochemical properties distinct from those of tacrolimus

Transplantation
L B PetersonG J Wiederrecht

Abstract

Tacrolimus (FK506) is an immunosuppressive drug 50-100 times more potent than cyclosporine (CsA), the current mainstay of organ transplant rejection therapy. Despite being chemically unrelated, CsA and tacrolimus exert their immunosuppressive effects through the inhibition of calcineurin (CaN), a critical signaling molecule during T-lymphocyte activation. Although numerous clinical studies have proven the therapeutic efficacy of drugs within this class, tacrolimus and CsA also have a strikingly similar profile of unwanted side effects. Our objective has been to identify a less toxic immunosuppressant through the modification of ascomycin (FK520). Quantitative in vitro immunosuppression and toxicity assays have demonstrated (see the accompanying article, p. 18) that we achieved our goal with L-732,531 (indolyl-ascomycin; indolyl-ASC), a 32-O-(1-hydroxyethylindol-5-yl) ascomycin derivative with an improved therapeutic index relative to tacrolimus. We report that the attributes of indolyl-ASC may result from its distinctive biochemical properties. In contrast to tacrolimus, indolyl-ASC binds poorly to FK506 binding protein 12 (FKBP12), the major cytosolic receptor for tacrolimus and related compounds. However, the stability of the...Continue Reading

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Citations

Oct 25, 2001·Analytical Biochemistry·C W CarrerasD V Santi
Aug 18, 1999·Bioorganic & Medicinal Chemistry Letters·M T GouletW H Parsons
Aug 18, 1999·Bioorganic & Medicinal Chemistry Letters·H M ArmstrongW H Parsons
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Feb 3, 1998·Transplantation·F J DumontM Wyvratt
Oct 29, 2009·Cell Communication and Signaling : CCS·Matthias Sieber, Ria Baumgrass
Mar 5, 2004·Expert Opinion on Investigational Drugs·Alexander M Marsland, Christopher E M Griffiths
Jan 21, 2014·American Journal of Ophthalmology·Abdulrahman Mohammed Al-Amri
Jul 23, 2003·The Journal of Biological Chemistry·Olivier MignenTrevor J Shuttleworth
Aug 17, 2002·The Journal of Pharmacology and Experimental Therapeutics·W P RevillB G Gold
Jul 24, 1998·Archives of Biochemistry and Biophysics·S P Salowe, J D Hermes

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