X-RAY STRUCTURE OF THE COMPLEX FKBP12/RAD AT 1.8A RESOLUTION
(RAD IS A NEW IMMUNOSUPPRESSIVE DERIVATIVE OF RAPAMYCIN FROM NOVARTIS PHARMA AG)

Jörg Kallen1, Richard Sedrani2 , Sylvain Cottens2, Walter Schuler2

1Novartis Pharma AG, Dept. of Core Technology, CH-4002, Basel, Switzerland
2Novartis Pharma AG, Dept. of Transplantation, CH-4002, Basel, Switzerland

Keywords: FKBP12, rapamycin, immunosuppression

The immunosuppressive macrolide rapamycin (RAP) has attracted interest in recent years because of its immunosuppressive properties, but this complex natural product exhibits unfavourable physicochemical properties. We therefore embarked on a program aimed at overcoming these difficulties by chemical derivation of RAP. Alkylation of the hydroxyl (O-alkylation) in either position 28 or 40 was undertaken. Methylation of the C28 hydroxyl led to a compound which still binds well to its immunophilin FKBP12, but exhibits no immunosuppressive activity anymore. Alkylation of the C40 hydroxyl, on the other hand, led to various FKBP12-binding, immunosuppressive derivatives, among which the compound 40-O-(2-hydroxy)ethylrapamycin (RAD) was selected for development. RAD is presently undergoing clinical trials for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.

Here we present the 1.8A X-ray structure of the complex FKBP12/RAD and show a comparison with the complex FKBP12/RAP. In addition the structural explanation is shown on why 28-O-methylrapamycin is not immunosuppressive anymore (and why RAD still is immunosuppressive), in terms of modelled interactions of the FKBP12/ligand complexes with the target-protein FRAP (=mTOR).

  1. Kallen J., Sedrani R., Cottens, S."X-ray Crystal Structure of 28-O-Methylrapamycin complexed with FKBP12: Is the Cyclohexyl Moiety Part of the Effector Domain of Rapamycin?", J. Am. Chem. Soc., 118 , 5857-5861, 1996.
  2. Choi J., Chen J., Schreiber S., Clardy J. "Structure of the FKBP12-Rapamycin Complex Interacting with the Binding Domain of Human FRAP", Science, 273, 239-242, 1996.
  3. Sedrani R., Cottens S., Kallen J., Schuler W. "Chemical Modification of Rapamycin: The Discovery of SDZ RAD" submitted to Transplant.Proc.1998.