Regulation of gene expression by synthetic dimerizers with novel specificity.
New synthetic chemical inducers of dimerization, comprising homodimeric FKBP ligands with engineered specificity for the designed point mutant F36V, have been evaluated for inducing targeted gene expression in mammalian cells. Structure-activity studies indicated that high-affinity dimerizers such as AP1903 are ineffective, perhaps due to kinetic trapping of non-productive dimers, whereas lower-affinity molecules, exemplified by AP1889 and AP1966, potently activate transcription.
Yang
Wu
W
ARIAD Gene Therapeutics, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA.
Keenan
Terence P
TP
Rozamus
Leonard W
LW
Wang
Xiurong
X
Rivera
Victor M
VM
Rollins
Carl T
CT
Clackson
Tim
T
Holt
Dennis A
DA
D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009930:Organic Chemicals; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
C119717:AP 1510; D003432:Cross-Linking Reagents; D009930:Organic Chemicals; C423866:AP 1903 reagent; D016559:Tacrolimus