Open AccessOne-step Heck Reaction Generates Nonimmunosuppressive FK506 Analogs for Pharmacological BMP Activation
Author(s) -
Yuefan Wang,
Brandon Peiffer,
Qi Su,
Jun O. Liu
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00144
Subject(s) - calcineurin , fkbp , heck reaction , chemistry , combinatorial chemistry , drug discovery , computational biology , microbiology and biotechnology , biochemistry , catalysis , biology , palladium , medicine , transplantation , surgery
FKBP12 ligands such as FK506 have been shown to activate the BMP signaling pathway and facilitate tissue regeneration. However, the immunosuppressive activity of FK506 limits its clinical application. Using Heck reaction, we generated nonimmunosuppressive analogs of FK506 by fusing heterocycles to the calcineurin (CN) binding domain of FK506. Structure-activity relationships provided novel mechanistic insights into the FK506-CN interaction that can be exploited for rational design of future analogs.