Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility

Guan, Jane; Zhou, Wei; Hafner, Marc; Blake, Robert A.; Chalouni, Cécile; Chen, Irene P.; Bruyn, Tom De; Giltnane, Jennifer M.; Hartman, Steven J.; Heidersbach, Amy; Houtman, René; Ingalla, Ellen; Kategaya, Lorn; Kleinheinz, Tracy; Li, Jun; Martin, Scott E.; Modrušan, Zora; Nannini, Michelle; Oeh, Jason; Ubhayakar, Savita; Wang, Xiaojing; Wertz, Ingrid E.; Young, Amy; Yu, Mamie; Sampath, Deepak; Hager, Jeffrey H.; Friedman, Lori S.; Daemen, Anneleen; Metcalfe, Ciara

doi:10.1016/j.cell.2019.06.026

Cited by 158 publications

(164 citation statements)

References 68 publications

(68 reference statements)

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“…These data raise the question whether the current path(s) of SERD development place unnecessary emphasis on potent and efficient downregulation of the receptor without equal attention to the efficacy of ER inhibition independent of receptor degradation. Furthermore, a recent study has reported that the efficacy of fulvestrant and additional SERDs are mediated by their ability to slow receptor mobility as opposed to their ability to downregulate ER [42]. In essence, the imperative to develop a SERD may result in the unnecessary omission of potentially tolerable complete antagonists and/or high affinity SERMs.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy

Wardell

Yllanes

Chao

et al. 2019

Breast Cancer Res Treat

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Purpose Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first-or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity. Methods Three xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation. Results A clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development. Conclusion The use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy

Wardell

Yllanes

Chao

et al. 2019

Breast Cancer Res Treat

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“…The impact of these differences in ER target gene activation remain to be explored but could suggest that cross-resistance between different classes of SERDs can be avoided. Recent studies have indicated that in addition to receptor degradation, ER mobility is differentially impacted by sub-classes of SERMs and SERDs, and that compounds impeding mobility are more efficacious antagonists [35]. The impact of G1T48 on ER mobility is not currently known; however, our studies establish that G1T48 has very low intrinsic ER agonist activity.…”

Section: Discussionmentioning

confidence: 51%

“…The most active SERDs share common chemical features: either (a) a steroidal backbone (e.g., fulvestrant, RU58,668) or (b) an acrylic acid side chain (GW7604, GDC-0810, AZD9496) [29,31,32,40,56,57]. Additional ER antagonists with novel chemical structures have also been reported to exhibit SERD properties [35,36,58], but none has yet gained FDA approval and some have been discontinued due to adverse effects or for undisclosed reasons [29-36, 40, 56]. We have identified a novel, orally bioavailable SERD, G1T48, that contains both a steroidal backbone and an acrylate side chain.…”

Section: Discussionmentioning

confidence: 99%

“…Novel ER antagonists with SERD activity have recently been described, but clinical development of these compounds has thus far been limited due to unanticipated side effects or for undisclosed reasons [29][30][31][32][33][34][35][36]. We sought to identify an orally bioavailable SERD using the chemical backbone of raloxifene as a starting point, since this SERM has demonstrated a favorable safety profile in the clinical setting of breast cancer prevention and osteoporosis treatment [37,38].…”

Section: G1t48 Is Similar To Fulvestrant In Its Ability To Downregulamentioning

confidence: 99%

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

Andreano

Wardell

Baker

et al. 2020

Breast Cancer Res Treat

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Purpose The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER. Methods The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo). Results G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib. Conclusions These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

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“…GPCR ligand: G protein-coupled receptors, also includes Dopamine D3(So et al, 2020)  Ion channel modulator: Ion channel modulator, is a type of drug that can modulates ion channels(Churchill et al, 2019)  Kinase inhibitor: Represent a type of enzyme inhibitor that can block the action of a protein kinases. Protein kinases are enzymes that add a Phosphate (PO4) group to a protein and can modulate its function(Xie et al, 2020)  Nuclear receptor ligands: Are active proteins in the nucleus of cells(Guan et al, 2019)  Enzyme inhibitor: Is a substance that binds to an enzyme to decrease its activity  Protease inhibitors: Are a class of antiviral drugs used in the treatment of HIV(Zhang et al, 2019b) The chemical structure of metoclopramide…”

mentioning

confidence: 99%

The Development of New Molecules Having Antiemetic Activity Using Molecular Modeling

Kanouni¹,

Benguerba²

2019

Current Research in Bioinformatics

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The solubility of a drug in water or in the blood represents the most desired parameter in medicine. Our aim is to obtain molecules with properties more effective than those of metoclopramide. In this work, two molecules with high solubility are constructed. Metoclopramide (a benzamide derivative) is a dopamine receptor antagonist used as an antiemetic drug. Its solubility in water is 200 mg/L at 25°C. In this work, we will develop two other molecules that have the same therapeutic activity of metoclopramide with a higher solubility in water, therefore in the blood, without affecting the other properties. The two molecules developed by molecular modeling with a chemical modification of the OH group of metoclopramide have a high solubility: approximately 3 times and 8 times that of metoclopramide. For the other physicochemical properties, there is a great similarity between the molecules. Thus, the two proposed molecules will have antiemetic activity, the second molecule will be more favorable because of its higher solubility and the number of HBA and HBD.

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Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility

Cited by 158 publications

References 68 publications

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy

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

The Development of New Molecules Having Antiemetic Activity Using Molecular Modeling

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