Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

Abstract

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

Dual mechanism estrogen receptor inhibitors

“…S1F). To our surprise, the side chain of [F]-OC2-Pip (19) did not point towards h12, but instead exited between h8 and h11, where it is stabilized by H-bonds with h11 His524 (Fig. 1D, Fig.…”

“…To test whether the compounds were effective against the constitutively active Y537S-ER that drives treatment-resistant metastatic disease and reduces the potency of antiestrogens, we tested the compounds with this receptor. Several of the piperidines were very efficacious (16)(17)(18)(19), as were the [F]-AcrEster and [F]-RU compounds (21 and 27) ( Fig. 1G-H, Fig.…”

“…Newer, orally active SERDs under clinical development have acrylate side chains ( Fig. S1C), again having a 2carbon linker but now to a carboxyl group (12,(15)(16)(17)(18)(19)(20). Thus, both FDA-approved SERMs and potential oral SERD replacements for fulvestrant contain a single, carefully positioned aminoalkyl or acrylate side chain that through direct interaction with helix 12 (h12) in the ER ligand binding domain (LBD), moves it to disrupt the surface binding site for transcriptional coactivators that drive proliferative gene expression, thus operating by a direct antagonism mechanism of action.…”

Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines

“…The gold standard treatment in this type of BC is the hormone adjuvant therapy, which either suppresses estrogen production (aromatase inhibitors) or modulates/degrades the ERα (SERMs/SERDs). The prolonged exposure to these therapies, usually administered consecutively for 5–10 years' time-frame, leads to resistance in half of all luminal BCs after 5 years, in spite of the ERα expression (Toy et al, 2017; Fanning et al, 2018; Busonero et al, 2019; Spinello et al, 2019b).…”

“…Targeted therapy counteracting mERα is a current object of intense preclinical and early clinical interest, as also evidenced by the significant number of studies aiming at identifying orally bioavailable SERDs, eventually able to overcome resistance (De Savi et al, 2015; Fanning et al, 2018; Hamilton et al, 2018; Sharma et al, 2018; Kahraman et al, 2019; Scott et al, 2019). Among these GDC-810, AZD9496 ( 5 ; Figure 1) (hereafter AZD, a drug in preclinical use as oral SERD, for which a first clinical study have been recently accomplished) (Weir et al, 2016; Hamilton et al, 2018), and LSZ102 have been identified (Scott et al, 2019).…”