2. Academic Validation
  3. Clozapine as an E3 Ligand for PROTAC Technology

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

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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