2. Academic Validation
  3. Synthesis and biological evaluation of niclosamide PROTACs

Synthesis and biological evaluation of niclosamide PROTACs

  • Bioorg Med Chem Lett. 2022 Sep 15:72:128870. doi: 10.1016/j.bmcl.2022.128870.
Erick Munoz 1,  Guanglin Chen 1,  Ahamed Hossain 2,  Sitong Wu 1,  Esveidy Oceguera Nava 1,  Jasmine Hang 1,  Tong Lee 1,  Qiang Zhang 2,  Guangdi Wang 3,  Qiao-Hong Chen 4
Affiliations

Affiliations

  • 1 Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
  • 2 Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
  • 3 Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. Electronic address: gwang@xula.edu.
  • 4 Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. Electronic address: qchen@csufresno.edu.
PMID: 35772635 DOI: 10.1016/j.bmcl.2022.128870
Abstract

Roughly 268,000 new cases of prostate Cancer and 34,000 deaths from prostate Cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen Receptor is a key protein in the proliferation and survival of prostate Cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate Cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology. PROTACs are hetero-bifunctional molecules where one end binds to a protein of interest and the Other to an E3 Ligase ligand, initiating the Ubiquitin-Proteasome Pathway for protein degradation. Two PROTACs with niclosamide as Androgen Receptor ligand and VHL-032 as the E3 Ligase ligand have been designed and synthesized for suppressing proliferation of androgen receptor-positive prostate Cancer cells via degrading Androgen Receptor. The in vitro antiproliferative assessment suggested that they can selectively suppress PC-3, LNCaP, and 22Rv1 prostate Cancer cell proliferation, but cannot inhibit DU145 cell proliferation. However, the mechanism of both compounds in suppressing prostate Cancer cell proliferation is not through the AR PROTAC mechanism because they did not degrade AR in our Western Blotting assay up to 1 µM.

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