Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells

Abstract

Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells

“…Interestingly, although T6I-29-1A structurally is more SERM-like, we did not observe any change in uterine weights in any study, even with the highest dosing of T6I-29-1A. This agrees with the reduced alkaline-phosphatase activities that were previously observed in Ishikawa endometrial cells [25]. Therefore, while T6I-29-1A does not induce ERα degradation like a SERM, it does not have the uterine-stimulating liabilities of SERMs like tamoxifen.…”

Pharmacokinetic Analysis of [18F]FES PET in the Human Brain and Pituitary Gland

“…Elacestrant was developed as a selective estrogen receptor degrader that crosses the blood–brain barrier for the treatment of estrogen receptor positive breast cancer brain metastases. The drug was shown to competitively bind to ERs [ 11 ] in the same binding pocket as estrogen and [ 18 F]FES [ 12 ]. The study was approved the independent ethics committee of the foundation “evaluation of ethics in biomedical research” (CCMO code: NL49312.056.14) and was performed in accordance with standards for Good Clinical Practice, in full compliance with the principles of the 1964 Declaration of Helsinki.…”

New generation estrogen receptor-targeted agents in breast cancer: present situation and future prospectives

“…Several clinical SERMs, such as tamoxifen, raloxifene, and lasofoxifene, contain a basic side chain that emerges from the ER LBD pocket and relocates h12 from the agonist conformation to the antagonist conformation (Figure 5a) [52,53]. Early clinical data of new SERDs featuring acrylic acid side chains did not yield encouraging results with respect to efficacy and tolerability, leading to the termination of further development for most of these compounds [54].…”