2. Academic Validation
  3. Discovery of Thieno[2,3- e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability

Discovery of Thieno[2,3- e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability

  • J Med Chem. 2022 Apr 14;65(7):5724-5750. doi: 10.1021/acs.jmedchem.2c00008.
Zhengyu Lu 1 2,  Yangzhi Cao 1 2,  Dan Zhang 1,  Xin Meng 1,  Bin Guo 1 2,  Deyu Kong 3,  Yushe Yang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
PMID: 35357160 DOI: 10.1021/acs.jmedchem.2c00008
Abstract

Endocrine therapies in the treatment of early and metastatic Estrogen Receptor α positive (ERα+) breast Cancer (BC) are greatly limited by de novo and acquired resistance. Selective Estrogen Receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast Cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.

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