Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist.
Protein knockdown can be achieved by the use of a small molecule that possesses affinity for both the target protein and ubiquitin ligase. We have designed such a degradation-inducing molecule targeting cIAP1 and CRABP-II, which are involved in proliferation of several cancer cell lines and in neuroblastoma growth, respectively. As a CRABP-II-recognizing moiety, all-trans retinoic acid (ATRA, 3), a physiological ligand of CRABP, was chosen. As a cIAP1-recognizing moiety, MV1 (5), which is a cIAP1/cIAP2/XIAP pan-ligand, was chosen. Although cIAP1 itself possesses ubiquitin ligase activity, we expected that its decomposition would be efficiently mediated by related molecules, including cIAP2 and XIAP, which also possess ubiquitin ligase activity. The designed degradation inducer 6, in which ATRA (3) and MV1 (5) moieties are connected via a linker, was synthesized and confirmed to induce efficient degradation of both cIAP1 and CRABP-II. It showed potently inhibited the proliferation of IMR32 cells.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Yukihiro
Y
Itoh
Minoru
M
Ishikawa
Risa
R
Kitaguchi
Keiichiro
K
Okuhira
Mikihiko
M
Naito
Yuichi
Y
Hashimoto
D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*
D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D009842:Oligopeptides; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D020169:Caspases