Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen

Loren, Guillem; Espuny, Irene; Lope, Alicia Llorente; Donoghue, Craig; Gomis, Roger R.; Riéra, Antoni

doi:10.1016/j.ejmech.2022.114770

Cited by 15 publications

(9 citation statements)

References 49 publications

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“…2e,f ). Based on an induced degradation of ER using an ER-specific PROTAC 24 in MCF7 ER + BCa cells, we confirmed the specificity of the MAF–ER interactions (Fig. 2e–g ).…”

Section: Resultssupporting

confidence: 73%

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis

Llorente,

Blasco,

Espuny

et al. 2023

Nat Cell Biol

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MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.

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“…2e,f ). Based on an induced degradation of ER using an ER-specific PROTAC 24 in MCF7 ER + BCa cells, we confirmed the specificity of the MAF–ER interactions (Fig. 2e–g ).…”

Section: Resultssupporting

confidence: 73%

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis

Llorente,

Blasco,

Espuny

et al. 2023

Nat Cell Biol

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“…[73] This example, clearly demonstrates that the introduction of a triazole ring via click chemistry cannot be a one-size-fits-all-solution. On the other hand, CuAAC were profitably applied in the development of PROTACs targeting, among others, estrogen receptor alpha (ERα), [74] Fms-like tyrosine receptor kinase 3 (FLT3), [75] or cyclin-dependent kinase 6 (CDK6). [76]…”

Section: Cuaac Reaction In the Synthesis Of New Protacsmentioning

confidence: 99%

Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?

Pasieka,

Diamanti,

Uliassi

et al. 2023

ChemMedChem

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Click chemistry is universally recognized as a powerful strategy for the fast and precise assembly of diverse building blocks. Targeted Protein Degradation (TPD) is a new therapeutic modality based on heterobifunctional small‐molecule degraders that provides new opportunities to medicinal chemists dealing with undruggable targets and incurable diseases. Here, we highlight how very recently the TPD field and that of click chemistry have merged, opening up the possibility for fine‐tuning the properties of a degrader, chemically assembled through a “click” synthesis. By reviewing concrete examples, we want to provide the reader with the insight that the application of click and bioorthogonal chemistry in the TDP field may be a winning combination.

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“…Because of their high molecular weights and often poor physicochemical properties, the development of highly potent and orally bioavailable ER PROTACs has been challenging. − However, extensive research has led to the discovery of ARV-471 as an orally bioavailable ER PROTAC degrader . In preclinical in vivo studies, ARV-471 demonstrated superior anti-tumor activity compared to fulvestrant .…”

Section: Introductionmentioning

confidence: 99%

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

Chen,

Hu,

Rej

et al. 2023

J. Med. Chem.

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Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.

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Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen

Cited by 15 publications

References 49 publications

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis

Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

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