1. Academic Validation
  2. Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation

Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation

  • J Biol Chem. 2018 May 4;293(18):6776-6790. doi: 10.1074/jbc.RA117.001091.
Nobumichi Ohoka 1 Yoko Morita 2 Katsunori Nagai 2 Kenichiro Shimokawa 2 Osamu Ujikawa 2 Ikuo Fujimori 2 Masahiro Ito 2 Youji Hayase 2 Keiichiro Okuhira 1 Norihito Shibata 1 Takayuki Hattori 1 Tomoya Sameshima 2 Osamu Sano 2 Ryokichi Koyama 2 Yasuhiro Imaeda 2 Hiroshi Nara 2 Nobuo Cho 2 Mikihiko Naito 3
Affiliations

Affiliations

  • 1 From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa 210-9501 and.
  • 2 the Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa 251-8555, Japan.
  • 3 From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa 210-9501 and miki-naito@nihs.go.jp.
Abstract

Aberrant expression of proteins often underlies many diseases, including Cancer. A recently developed approach in drug development is small molecule-mediated, selective degradation of dysregulated proteins. We have devised a protein-knockdown system that utilizes chimeric molecules termed specific and nongenetic IAP-dependent protein erasers (SNIPERs) to induce ubiquitylation and proteasomal degradation of various target proteins. SNIPER(ER)-87 consists of an inhibitor of Apoptosis protein (IAP) ligand LCL161 derivative that is conjugated to the Estrogen Receptor α (ERα) ligand 4-hydroxytamoxifen by a PEG linker, and we have previously reported that this SNIPER efficiently degrades the ERα protein. Here, we report that derivatization of the IAP ligand module yields SNIPER(ER)s with superior protein-knockdown activity. These improved SNIPER(ER)s exhibited higher binding affinities to IAPs and induced more potent degradation of ERα than does SNIPER(ER)-87. Further, they induced simultaneous degradation of cellular inhibitor of Apoptosis protein 1 (cIAP1) and delayed degradation of X-linked IAP (XIAP). Notably, these reengineered SNIPER(ER)s efficiently induced Apoptosis in MCF-7 human breast Cancer cells that require IAPs for continued cellular survival. We found that one of these molecules, SNIPER(ER)-110, inhibits the growth of MCF-7 tumor xenografts in mice more potently than the previously characterized SNIPER(ER)-87. Mechanistic analysis revealed that our novel SNIPER(ER)s preferentially recruit XIAP, rather than cIAP1, to degrade ERα. Our results suggest that derivatized IAP ligands could facilitate further development of SNIPERs with potent protein-knockdown and cytocidal activities against Cancer cells requiring IAPs for survival.

Keywords

ERalpha; SNIPER; X-linked inhibitor of apoptosis protein (XIAP); estrogen receptor; proteasome; protein knockdown; tumor therapy; ubiquitin.

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