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Regulation of biological events using novel compounds

  • US 6,649,595 B2
  • Filed: 02/12/2001
  • Issued: 11/18/2003
  • Est. Priority Date: 06/07/1995
  • Status: Expired due to Term
First Claim
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1. A method for multimerizing chimeric proteins in cells which comprises:

  • (a) providing cells which contain;

    (i) a first recombinant nucleic acid encoding a first chimeric protein which binds to rapamycin or an analog thereof and which comprises at least one FK506-binding protein (FKBP) domain and at least one protein domain heterologous thereto, wherein the FKBP domain comprises a naturally occurring FKBP or a variant thereof in which up to 10 amino acid residues have been deleted, inserted, or replaced with substitute amino acids;

    (ii) a second recombinant nucleic acid encoding a second chimeric protein which forms a complex with both (a) rapamycin or a rapamycin analog and (b) the first chimeric protein, and which comprises at least one FKBP;

    rapamycin binding (FRB) domain and at least one domain heterologous thereto, wherein the FRB domain comprises a peptide sequence selected from a naturally occurring FRB domain, or a variant thereof in which up to 10 amino acid residues have been deleted, inserted, or replaced with substitute amino acids; and

    , (b) contacting the cells with a rapalog which forms a complex containing itself and at least one molecule of each of the first and second chimeric proteins, where the rapalog has an immunosup-pressive effect less than 0.01 times that of rapamycin and comprises the substructure of formula I;

    embedded imagebearing one or more optional substituents, optionally unsaturated at one or more carbon—

    carbon bonds spanning carbons 1 through 8, as a substantially pure stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable derivative thereof.

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