Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges

Boisen, M.M.; Andersen, Courtney; Sreekumar, Sreeja; Stern, Andrew M.; Oesterreich, Steffi

doi:10.1016/j.mce.2015.04.035

Cited by 9 publications

(5 citation statements)

References 157 publications

(59 reference statements)

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“…The films described herein demonstrated good structural stability in phosphate buffer solution (PBS) at 37 °C. Besides, SNC/CS multilayer thin films exhibited pH-induced swelling/deswelling behaviors, leading to an on/off “switch” for the release of fulvestrant, a Food and Drug Administration (FDA)-approved selective estrogen receptor down-regulator agent for the treatment of metastatic breast cancer . To the best of our knowledge, this work represents the first study on controlled release of fulvestrant from electrostatically assembled NC-incorporated LbL films.…”

Section: Introductionmentioning

confidence: 91%

“…Besides, SNC/CS multilayer thin films exhibited pH-induced swelling/deswelling behaviors, leading to an on/off "switch" for the release of fulvestrant, a Food and Drug Administration (FDA)-approved selective estrogen receptor down-regulator agent for the treatment of metastatic breast cancer. 33 To the best of our knowledge, this work represents the first study on controlled release of fulvestrant from electrostatically assembled NC-incorporated LbL films. Due to the electrostatic interaction between the oppositely charged components, positively charged chitosan effectively bridged negatively charged alginate/chitosan/ alginate-modified SNCs within the films.…”

Section: ■ Introductionmentioning

confidence: 91%

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Electrostatically Assembled Multilayered Films of Biopolymer Enhanced Nanocapsules for on-Demand Drug Release

Chu

Wang

et al. 2019

ACS Appl. Bio Mater.

155

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We describe layer-by-layer (LbL) buildup and pH-responsive behavior of multilayer films of alginate/chitosan/ alginate -modified silica nanocapsules (SNCs) and chitosan (CS) biopolymers via electrostatic interaction. The SNC/CS films exhibit pH-triggered swelling/deswelling transitions under physiological conditions. Fulvestrant, an FDA-approved selective estrogen receptor down-regulator agent for the treatment of breast cancer, was encapsulated in SNCs and further incorporated into the LbL films. The drug release profile from the films was dependent on pH value of the surrounding environment. At pH 7.4, the films were able to efficiently entrap fulvestrant, with only ∼38% released in 120 days, whereas exposure to a lower pH value (pH 5.0) triggered faster fulvestrant release in phosphate buffer solution at 37 °C. Atomic force microscopy and ellipsometry showed that the films retained their structural integrity in PBS after several swelling/ deswelling cycles. SNC/CS LbL films demonstrated repeated on/off drug release under external triggers, allowing consistent fulvestrant release (∼14−18% of encapsulated fulvestrant released for each cycle) over a 10-day period without significant change in drug release rate. This work demonstrates the first proof-of-concept platform of SNC-incorporated films with welldefined internal structure, good stability, high loading capacity, and controlled/sustained release profile for on-demand drug delivery. With great versatility to use various active compounds and building blocks, the films may have high potential for broad applications such as implantable biosensors and antifouling coatings.

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Section: Introductionmentioning

confidence: 91%

Section: ■ Introductionmentioning

confidence: 91%

Electrostatically Assembled Multilayered Films of Biopolymer Enhanced Nanocapsules for on-Demand Drug Release

Chu

Wang

et al. 2019

ACS Appl. Bio Mater.

155

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“…2-(1H-Indol-3-yl)cyclopentan-1-amine (10). To a solution of 2-(1H-indol-3-yl)cyclopentan-1-one (9; 4.78 g, 24.2 mmol) in methanol (60 mL) was added ammonium acetate (20.18 g, 262 mmol) and sodium cyanoborohydride (1.67g, 26.42 mmol).…”

Section: -((1-tosyl-1h-indol-3-yl)methyl)cyclopropan-1-amine (5)mentioning

confidence: 99%

“…Several companies are engaged in the exploration of novel orally available SERDs, and several new compounds have entered clinical trials recently, including GW-5638 (6), GW-7604 (7), GDC-0810 (8), AZD9496 (9), and LSZ-102 (10). 24−28 When the basic side chain of tamoxifen is substituted by acrylic acid group, GW-5638 can be obtained, which improves the antagonistic activity and induces the degradation of ER.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Nowadays, endocrine therapy is the main treatment to estrogen receptor positive breast cancer . Conceptually, on the basis of related targets of breast cancer and estrogen signaling pathways, the antiestrogen drugs can be mainly divided into three types: aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs). , The aromatase can catalyze the androstenedione into estrogen in vivo; thus, aromatase inhibitors ( 1 , letrozole; 2 , anastrozole; Figure ) indicate antitumor activity by inhibiting the synthesis of estrogen which is responsible for the key biosynthetic step in the formation of mitogenic molecules . SERMs can bind to the ligand binding region (LBD) of ER competitively and form a dimer complex, which changes the conformation of ERα and results in blocking of the interaction between coactivator and activating function-2 (AF2) of ERα, and finally can block the estrogen signaling pathway and inhibit tumor formation .…”

Section: Introductionmentioning

confidence: 99%

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Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ERα+ Breast Cancer

Zhang

Wang

et al. 2021

J. Med. Chem.

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The estrogen receptor α (ERα) is identified as an effective target for the treatment of ERα+ breast cancer; thus, discovery of novel selective estrogen receptor degraders (SERDs) are developed as an effective method to overcome the resistance of breast cancer. Herein, the hot-spot residues for protein–ligand interaction between SERDs and ERα are analyzed by molecular dynamic simulation technology, focusing on the hot-spot residues for four series of designed and synthesized SERDs. SAR studies revealed that while the acrylic acid moiety of AZD9496 is scaffold hopping into benzoic acid, compound D24 exhibits potent binding affinity with ERα, good degradation efficacy of ERα, and inhibitory effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast cancer xenograft model in vivo, favorable pharmacokinetic properties, excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation.

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Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs)

Zhang

et al. 2019

European Journal of Medicinal Chemistry

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Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges

Cited by 9 publications

References 157 publications

Electrostatically Assembled Multilayered Films of Biopolymer Enhanced Nanocapsules for on-Demand Drug Release

Electrostatically Assembled Multilayered Films of Biopolymer Enhanced Nanocapsules for on-Demand Drug Release

Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ERα+ Breast Cancer

Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs)

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