2. Academic Validation
  3. Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models

Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models

  • Arch Pharm (Weinheim). 2022 May;355(5):e2100467. doi: 10.1002/ardp.202100467.
Lukas M Gockel 1,  Vladlena Pfeifer 1,  Fabian Baltes 1,  Rafael D Bachmaier 2,  Karl G Wagner 2,  Gerd Bendas 1,  Michael Gütschow 3,  Izidor Sosič 4,  Christian Steinebach 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, Bonn, Germany.
  • 2 Department of Pharmaceutical Technology, Pharmaceutical Institute, Bonn, Germany.
  • 3 Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, Bonn, Germany.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
PMID: 35128717 DOI: 10.1002/ardp.202100467
Abstract

Although the Androgen Receptor (AR) is a validated target for the treatment of prostate Cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting Cereblon, we were able to demonstrate the potent degradation of AR in lung Cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in Lung Cancer Models.

Keywords

CRBN; PROTAC; androgen receptor; enzalutamide; medicinal chemistry.

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