2. Academic Validation
  3. Developing orally active estrogen receptor degraders by conjugation of boronic tamoxifen and cereblon ligands

Developing orally active estrogen receptor degraders by conjugation of boronic tamoxifen and cereblon ligands

  • Eur J Med Chem. 2026 Oct 5:315:118956. doi: 10.1016/j.ejmech.2026.118956.
Xianyou Peng 1,  Ahamed Hossain 2,  Peng Ma 2,  Shanchun Guo 2,  Madhusoodanan Mottamal 2,  Changde Zhang 2,  Shilong Zheng 2,  Borui Kang 3,  Guangdi Wang 4
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Selenium Resource Research and Biological Application, Hubei Minzu University, Enshi, 445000, China; RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
  • 2 RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
  • 3 Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
  • 4 RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA. Electronic address: [email protected].
PMID: 42172929 DOI: 10.1016/j.ejmech.2026.118956
Abstract

Degradation of Estrogen receptor has been clinically proven effective in treating ER+ breast Cancer. Proteolysis-Targeting Chimeras (PROTACs) can degrade a target protein by engaging both the target protein and the E3 Ligase, bringing them into close physical proximity to effect ubiquitination and proteasomal degradation. We report the design and construction of ER PROTACs that link tamoxifen derivatives to a CRBN E3 ligand to achieve ER protein degradation. The ER degrading efficacy of the synthesized PROTACs was found to depend on the ER binding affinity, the linker structure, and the E3 ligand. Tamoxifen-4-boronic acid conjugated to lenalidomide through a rigid piperidine-methylene-piperazine linker was found to yield degraders that show nanomolar antiestrogenic potency and excellent oral bioavailability. The most active ER degrader with good pharmacokinetic profile, 4r, showed remarkable in vivo efficacy in blocking ER+ (both non-mutant and Y537S mutant) breast tumor growth as a monotherapy or in combination with CDK4/6 inhibitors.

Keywords

Boronic tamoxifen; Breast cancer; CRBN; E3 ligase; ER degrader; PROTAC.

Figures
Products