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

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.

Robust ERα-Targeted Near-Infrared Fluorescence Probe for Selective Hydrazine Imaging in Breast Cancer

“…The crystal structure of ERα LBD (PDB: 3ERD) was downloaded from PDB, and water molecules were removed. The crystallographic coordinate of probe 1 was established by Biochemoffice.…”

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

“…The resulting product was treated with TFA/DCM (2 mL/4 mL) at rt for 20 min, and then the solution was concentrated to a dryness, which was further lyophilized to give compound 2-(2,6-dioxopiperidin-3-yl)-6-(piperidin-4-yl)-6,7dihydropyrrolo [3,4- To a suspension of TFA salt of compound 51c (30 mg, 1.0 equiv) in DCE/DMF (4 mL/2 mL) was added intermediate 50g (32 mg, 1.2 equiv), and the mixture was stirred at rt for 6 h. NaBH(OAc) 3 (38 mg, 3.0 equiv) was then added into portions over 12 h, after which the reaction was kept stirring for another 12 h. The reaction mixture was concentrated under reduced pressure to remove most of the solvent DCE and purified by pre-HPLC (MeCN/H 2 O = 35−100% in 65 min) to afford a pure product. The resulting product was treated with TFA/ DCM (2 mL/4 mL) at rt for 3−4 h. Then the solution was concentrated to a dryness, which was further lyophilized to give the title compound 2- (22). The title compound 22 was prepared from intermediates 50g and 51d using a similar procedure for producing 21 from intermediates 50g and 51c, and it was afforded as a light-yellow solid (67% yield).…”

Recent advances in targeted protein degraders as potential therapeutic agents

“…Among them, the most representative and notable is the publication of monovalent degraders targeting ERɑ and AR. Previously, selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) that could directly antagonize ERα transcriptional activity or block estrogen biosynthesis were employed in the cure of ERα-positive breast cancer [ 72 ]. Lately, fulvestrant (36) (Fig.…”

“…Lately, fulvestrant (36) (Fig. 17 ), a selective estrogen receptor degrader, which binds and downregulates ER by inducing conformational instability could induce ERα degradation and overcome resistance to AIs and SERMs [ 13 , 72 ]. Until recently, Lu et al discovered a thieno[2,3‑ e ] indazole derivative as novel oral selective estrogen receptor degraders (SERDs) (37) (Fig.…”

“…Until recently, Lu et al discovered a thieno[2,3‑ e ] indazole derivative as novel oral selective estrogen receptor degraders (SERDs) (37) (Fig. 17 ) for the treatment of ER-positive breast cancer, which has been evaluated in preclinical trials [ 72 ].

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