TY - JOUR
T1 - Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist
AU - Itoh, Yukihiro
AU - Ishikawa, Minoru
AU - Kitaguchi, Risa
AU - Okuhira, Keiichiro
AU - Naito, Mikihiko
AU - Hashimoto, Yuichi
N1 - Funding Information:
The work described in this Letter was partially supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan , and the Japan Society for the Promotion of Science . This work was also supported financially by the Takeda Science Foundation and the Naito Foundation . We are grateful to Nippon Kayaku Co., especially Dr. Keiko Sekine, for providing MeBS ( 4 ), to HSRRB for providing IMR32 cells (IFO50283), and to Dr. Yukihide Tomari for help with Western blot detection.
PY - 2012/7/1
Y1 - 2012/7/1
N2 - 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.
AB - 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.
KW - CRABP-II
KW - Protein knockdown
KW - cIAP1
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U2 - 10.1016/j.bmcl.2012.04.134
DO - 10.1016/j.bmcl.2012.04.134
M3 - Article
C2 - 22658364
AN - SCOPUS:84862170982
SN - 0960-894X
VL - 22
SP - 4453
EP - 4457
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 13
ER -
