Discovery of Thieno[2,3- e ]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability.
Zhengyu LuYangzhi CaoDan ZhangXin MengBin GuoDeyu KongYushe YangPublished in: Journal of medicinal chemistry (2022)
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 6 H -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.
Keyphrases
- estrogen receptor
- wild type
- induced apoptosis
- squamous cell carcinoma
- small cell lung cancer
- small molecule
- cell cycle arrest
- white matter
- resting state
- metabolic syndrome
- young adults
- stem cells
- insulin resistance
- endoplasmic reticulum stress
- multiple sclerosis
- blood brain barrier
- functional connectivity
- skeletal muscle
- subarachnoid hemorrhage
- childhood cancer
- replacement therapy
- single cell
- smoking cessation