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

摘要

Endocrine therapies in the treatment of early and metastatic estrogen receptor alpha positive (ER alpha+) breast cancer (BC)are greatly limited byde novoand acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide newstrategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization ofLSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led usto identify compound40as the preferred candidate. In general, compound40showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ER alpha 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,40is being evaluated in preclinical trials

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