Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer

  • J Med Chem. 2024 Dec 12;67(23):21545-21567. doi: 10.1021/acs.jmedchem.4c02453.
Dan Zhang  1 ,  Zhengyu Lu  1 ,  Yongqi He  1  2 ,  Xin-Yu Leng  1  3 ,  Xin Meng  3 ,  Xiang Lei  1  2 ,  Deyu Kong  1 ,  Lulu Sun  1 ,  Wenhao Hu  4 ,  Yushe Yang  1  3
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3. School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
PMID: 39610216 DOI: 10.1021/acs.jmedchem.4c02453
Abstract

Selective Estrogen receptor degraders (SERDs) deplete the ER signaling pathway via antagonism and degradation of ERα and represent a promising strategy to tackle endocrine resistance. Here, we report a new class of SERDs by pharmacological evolution of a selective Estrogen receptor Modulator, lasofoxifene. The structure-activity relationship study and efforts to circumvent the issue of human ether-a-go-go-related gene led to the identification of compounds 51. This bifunctional compound displayed broad activity across a vast array of cell backgrounds and was capable of effectively degrading and antagonizing wild-type ERα and clinically relevant ERα mutants. 51 exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates 51 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.

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