Synthesis and structure–activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution

Gauthier, Sylvie F.; Cloutier, Julie; Dory, Yves L.; Favre, Alexandre; Mailhot, J; Ouellet, Catherine; Schwerdtfeger, A. E.; Mérand, Yves; Martel, Céline; Simard, Jacques; Labrie, Fernand

doi:10.1080/14756360500043448

Cited by 15 publications

(8 citation statements)

References 42 publications

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“…2b ). The unsubstituted pyrrolidine, OP-1156, induced AP activity 40%, in line with the increased uterine wet weight in ovariectomized mice previously reported for this compound 38 . In contrast to the antagonist activity observed for 3R-substituted pyrrolidine of OP-1074, the 3S-substituted analog, OP-1154, induced AP activity 39% and did not completely antagonize E2-stimulated AP activity.…”

Section: Resultssupporting

confidence: 85%

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

et al. 2018

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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.

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Section: Resultssupporting

confidence: 85%

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

et al. 2018

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“…Exploration of the side chains of dihydrobenzoxathiins compounds such as compound 23 is the foundation of the discovery of basic amino side chain SERDs (Figure ). − …”

Section: Recent Development Of Serdsmentioning

confidence: 99%

“…Exploration of the side chains of dihydrobenzoxathiins compounds such as compound 23 is the foundation of the discovery of basic amino side chain SERDs (Figure 7). 125 26) is one of the second generation of nonsteroidal acrylic acid SERDs developed from GW 5638 (24). In 2005, Wu et al reported two antiestrogens, compound 24 and its hydroxylated metabolite GW7604 (25), with a triphenylethylene scaffold similar to 4hydroxytamoxifen (Figure 8).…”

Section: Role Of Erα In the Mechanism Of Acquiredmentioning

confidence: 99%

Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer

Liu

2020

J. Med. Chem.

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Estrogen receptor (ER) plays important roles in gene transcription and the proliferation of ER positive breast cancers. Selective modulation of ER has been a therapeutic target for this specific type of breast cancer for more than 30 years. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have been demonstrated to be effective therapeutic approaches for ER positive breast cancers. Unfortunately, 30−50% of ER positive tumors become resistant to SERM/AI treatment after 3−5 years. Fulvestrant, the only approved selective estrogen receptor degrader (SERD), is currently an important therapeutic approach for the treatment of endocrine-resistant breast cancers. The poor pharmacokinetic properties of fulvestrant have inspired the development of a new generation of oral SERDs to overcome drug resistance. In this review, we describe recent advances in ERα structure, functions, and mechanisms of endocrine resistance and summarize the development of oral SERDs in both academic and industrial areas.

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“…EM-800 is a well-studied precursor of acolbifene which was found to be safe and tolerable [196,197]. It is orally active but lacks agonistic activity in the endometrium, thereby reducing the chances of developing uterine cancer [198][199][200]. The drug was found to have partial cross-resistance with tamoxifen [198].…”

Section: Selective Estrogen Receptor Modulators (Serms)mentioning

confidence: 99%

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

Bafna

Ban

Rennie

et al. 2020

IJMS

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Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.

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Synthesis and structure–activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution

Cited by 15 publications

References 42 publications

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

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

Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

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