Molecular Design, Synthesis, and Evaluation of SNIPER (ER) that Induces Targeted Protein Degradation of ERα

Nobumichi Ohoka; Hidetomo Yokoo; Keiichiro Okuhira; Yosuke Demizu; Mikihiko Naito

doi:10.1007/978-1-0716-1920-9_20

Molecular Design, Synthesis, and Evaluation of SNIPER (ER) that Induces Targeted Protein Degradation of ERα

Methods Mol Biol. 2022:2418:363-382. doi: 10.1007/978-1-0716-1920-9_20.

Authors

Nobumichi Ohoka^#¹, Hidetomo Yokoo^#², Keiichiro Okuhira^{1

3}, Yosuke Demizu², Mikihiko Naito^{4

5

6}

Affiliations

¹ Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan.
² Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan.
³ Department of Environment and Health Sciences, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
⁴ Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan. [email protected].
⁵ Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan. [email protected].
⁶ Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [email protected].

^# Contributed equally.

PMID: 35119675
DOI: 10.1007/978-1-0716-1920-9_20

Abstract

Manipulation of protein stability using small molecules has a great potential for both basic research and clinical therapy. Based on our protein knockdown technology, we developed chimeric degrader molecules SNIPER(ER)s that target the estrogen receptor alpha (ERα) for degradation via the ubiquitin-proteasome system. This chapter describes the design and synthesis of SNIPER(ER) compounds and methods for the evaluation of their activity in cellular systems and in a tumor xenograft model.

Keywords: Antitumor activity; Cell death; Estrogen receptor; Protein knockdown; SNIPER; Ubiquitin-proteasome system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms*
Cell Line, Tumor
Estrogen Receptor alpha* / genetics
Estrogen Receptor alpha* / metabolism
Female
Humans
Mice
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Ubiquitin / metabolism
Ubiquitination

Substances

Estrogen Receptor alpha
Ubiquitin
Proteasome Endopeptidase Complex