Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer

Abstract

Resistance to the selective estrogen receptor modulator (SERM) tamoxifen and to aromatase inhibitors that lower circulating estradiol occurs in up to 50% of patients, generally leading to an endocrine-independent ER+ phenotype. Selective ER downregulators (SERDs) are able to ablate ER and thus theoretically to prevent survival of both endocrine-dependent and independent ER+ tumors. The clinical SERD, fulvestrant, is hampered by intramuscular administration and undesirable pharmacokinetics. Novel SERDs were designed using the 6-OH-benzothiophene (BT) scaffold common to arzoxifene and raloxifene. Treatment-resistant (TR) ER+ cell lines (MCF-7:5C and MCF-7:TAM1) were used for optimization, followed by validation in the parent endocrine-dependent cell line (MCF-7:WS8), in 2D and 3D cultures, using ERα in-cell westerns, ERE-luciferase, and cell viability assays, with GDC-0810 (ARN-810) used for comparison. Two BT SERDs with superior in vitro activity to GDC-0810 were studied for bioavailability and shown to cause regression of a TR, endocrine-independent ER+ xenograft superior to GDC-0810.

A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers

“…As such, the direct interaction of the ligand with the L11-12 and, in particular, with the residues in the region 529–537, is crucial to exert an antagonistic/downregulator activity even in aggressive polymorphisms. This appears to be in line with recently identified ERα downregulators, which bear a carboxyl moiety pointing towards L11-12 29 and with the hydrophobic interactions with L536 observed for a potent antagonist with a new scaffold 30 .…”

BF3·SMe2 for Thiomethylation, Nitro Reduction and Tandem Reduction/SMe Insertion of Nitrogen Heterocycles

“…The methoxy‐bearing substrate 5o and methyl ester 5p both underwent rapid demethylation, which is in accordance with the known reactivity profile of BF 3 · SMe 2 (Scheme ) . Notably, treatment of 3‐quinolinecarboxaldehyde ( 5q ) led to the formation of the thioacetal product 8c and represents a valuable alternative to the use of methanethiol for the installation of this protecting group.…”

“…Importantly, this method is solvent and base‐free and requires the addition of only one reagent, making the process highly convenient. In addition, novel nitro reduction and cascade nitro reduction/thiomethylation processes have also been discovered showcasing BF 3 · SMe 2 as a surprisingly diverse reagent with uses far beyond its standard role as a demethylation and debenzylation, agent.…”

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

“…G1T48 incorporates an acrylic acid side chain ( Fig. 1a) [29,31,32,34,39,40], and was the product of structure-guided investigations, driven by activity in breast cancer cell lines [24]. G1T48 was first assessed for its ability to downregulate ER when compared to several benchmark SERMs and SERDs including fulvestrant [12,41].…”

“…Collectively, these data highlight an unmet need for a safe, orally bioavailable SERD with appropriate pharmaceutical properties. Herein we describe the preclinical development of G1T48 (rintodestrant), an orally bioavailable, potent, and selective non-steroidal ER antagonist and downregulator [24]. G1T48 was found to robustly inhibit ER activity in multiple in vitro models of endocrine therapy resistance, including those harboring ER mutations or growth factor activation.…”