Searching for an ideal SERM: Mining tamoxifen structure–activity relationships

Price, Sky; Bender, Sophie G.; Yahn, Rachel; Till, Nicholas A.; Varady, Sophia; LaLonde, Rebecca Lyn

doi:10.1016/j.bmcl.2021.128383

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…However, persistent therapy has been debated, especially if the duration exceeds five years. Therefore, tamoxifen remains the leading SERM, and interest in developing analogs with better anti-tumor activities and reduced toxicity continues [29].…”

Section: Selective Estrogen Receptor Modulatorsmentioning

confidence: 99%

Hormone, Targeted, and Combinational Therapies for Breast Cancers: From Humans to Dogs

Ke,

Lin,

Lin

2024

IJMS

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Breast cancer (BC) is the most frequent cancer in women. In female dogs, canine mammary gland tumor (CMT) is also the leading neoplasm. Comparative oncology indicates similar tumor behaviors between human BCs (HBCs) and CMTs. Therefore, this review summarizes the current research in hormone and targeted therapies and describes the future prospects for HBCs and CMTs. For hormone receptor-expressing BCs, the first medical intervention is hormone therapy. Monoclonal antibodies against Her2 are proposed for the treatment of Her2+ BCs. However, the major obstacle in hormone therapy or monoclonal antibodies is drug resistance. Therefore, increasing alternatives have been developed to overcome these difficulties. We systemically reviewed publications that reported inhibitors targeting certain molecules in BC cells. The various treatment choices for humans decrease mortality in females with BC. However, the development of hormone or targeted therapies in veterinary medicine is still limited. Even though some clinical trials have been proposed, severe side effects and insufficient case numbers might restrict further explorations. This difficulty highlights the urgent need to develop updated hormone/targeted therapy or novel immunotherapies. Therefore, exploring new therapies to provide more precise use in dogs with CMTs will be the focus of future research. Furthermore, due to the similarities shared by humans and dogs, well-planned prospective clinical trials on the use of combinational or novel immunotherapies in dogs with CMTs to obtain solid results for both humans and dogs can be reasonably anticipated in the future.

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Section: Selective Estrogen Receptor Modulatorsmentioning

confidence: 99%

Hormone, Targeted, and Combinational Therapies for Breast Cancers: From Humans to Dogs

Ke,

Lin,

Lin

2024

IJMS

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“…Randomised trials of tamoxifen versus other SERMs, synthesised in the hope of greater clinical activity, reported them to be either equally (idoxifene, toremifine) or less effective than tamoxifen (raloxifene, arzoxifene) in the treatment of advanced breast cancer [ 4 , 17 ]. Thus, tamoxifen retained its place as the lead SERM and there still remains interest in developing analogues of tamoxifen with greater activity and reduced toxicity [ 18 ].…”

Section: Development In Advanced Breast Cancermentioning

confidence: 99%

Tamoxifen evolution

Howell

2023

Br J Cancer

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“…Considering all mentioned above, deeper exploration needs to be conducted to identify new compounds with ideal antiestrogenic properties on ER+ BC and an improved therapeutic window [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen

Guerra-Rodríguez

López-Rojas

Amesty

et al. 2022

Cancers

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Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound 35 caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound 35 suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound 35 may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.

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Searching for an ideal SERM: Mining tamoxifen structure–activity relationships

Cited by 6 publications

References 30 publications

Hormone, Targeted, and Combinational Therapies for Breast Cancers: From Humans to Dogs

Hormone, Targeted, and Combinational Therapies for Breast Cancers: From Humans to Dogs

Tamoxifen evolution

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen

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