Clozapine as an E3 Ligand for PROTAC Technology

  • ACS Med Chem Lett. 2025 Jan 8;16(2):258-262. doi: 10.1021/acsmedchemlett.4c00500.
Reina Takano  1  2 ,  Nobumichi Ohoka  3 ,  Takashi Kurohara  2 ,  Noriaki Arakawa  4 ,  Kenji Ohgane  5 ,  Takao Inoue  3 ,  Hidetomo Yokoo  1 ,  Yosuke Demizu  1  2  6
Affiliations
  • 1. Graduate School of Medical Life Science, Yokohama City University, Kanagawa 210-9501, Japan.
  • 2. Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
  • 3. Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
  • 4. Division of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
  • 5. Department of Chemistry, Ochanomizu University, Tokyo 112-8610, Japan.
  • 6. Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science, Okayama University, Okayama 700-8530, Japan.
PMID: 39967646 DOI: 10.1021/acsmedchemlett.4c00500
Abstract

New ubiquitin Ligase (E3) ligands are crucial for developing proteolysis-targeting chimeras (PROTACs) to induce the degradation of a target protein. In this study, we developed a PROTAC using the antipsychotic drug clozapine as a new E3 ligand. First, a clozapine PROTAC targeting a model target HaloTag protein (Halo-PEG-Clozapine) was synthesized, and the PROTAC induced degradation of the HaloTag-fused protein in a Cell Culture system. Another clozapine PROTAC targeting the Cancer therapeutic target Estrogen receptor α (ERα) (Tamoxifen-PEG-Clozapine) was synthesized and induced degradation of the ERα protein in MCF-7 breast Cancer cells. Experiments with inhibitors and siRNAs showed that Tamoxifen-PEG-Clozapine degraded ERα via a ubiquitin-proteasome system that uses the ubiquitin protein Ligase E3 component N-recognin 5. These results indicate that clozapine is a promising E3 ligand that may expand the molecular design of PROTACs, contributing to the advancement of drug discovery by facilitating the degradation of disease-related proteins.

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