Design, synthesis and biological evaluation of nuclear receptor-degradation inducers.
Compounds that regulate the function(s) of nuclear receptors (NRs) are useful for biological studies and as candidate therapeutic agents. Most such compounds are agonists or antagonists. On the other hand, we have developed specific protein degradation inducers, which we designated as SNIPERs (Specific and Nongenetic IAPs-dependent Protein ERasers), for selective degradation of target proteins. SNIPERs are hybrid molecules consisting of an appropriate ligand for the protein of interest, coupled to a ligand for inhibitor of apoptosis proteins (IAPs), which target the bound protein for polyubiquitination and proteasomal degradation. We considered that protein knockdown with SNIPERs would be a promising alternative approach for modulating NR function. In this study, we designed and synthesized degradation inducers targeting retinoic acid receptor (RAR), estrogen receptor (ER), and androgen receptor (AR). These newly synthesized RAR, ER, and AR SNIPERs, 9, 11, and 13, respectively, were confirmed to significantly reduce the levels of the corresponding NRs in live cells.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Yukihiro
Y
Itoh
Risa
R
Kitaguchi
Minoru
M
Ishikawa
Mikihiko
M
Naito
Yuichi
Y
Hashimoto
D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D011944:Receptors, Androgen / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid