New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons

Wang, Lucia; Guillen, Valeria Sanabria; Sharma, Naina; Flessa, Kevin; Min, Jian; Carlson, Kathryn E.; Toy, Weiyi; Braqi, Sara; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.; Chandarlapaty, Sarat; Sharma, Abhishek

doi:10.1021/acsmedchemlett.8b00106

Cited by 49 publications

(29 citation statements)

References 33 publications

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“…58 Recently, a new PROTAC used nonsteroid selective ER degrader (SERD) was developed to generate more powerful and shorter active molecules to induce the degradation of ER. 66 On the PROTACs against AR, Crews group used enzalutamide to optimally link to a VHL ligand and named the hybrid molecule ARCC-4. 67 They showed that ARCC-4 induced the degradation of AR in not only all prostate cancer cell lines (VCaP, LNCaP, and 22Rv1) but also a breast cancer cell line (T47D).…”

Section: Targeting Nuclear Receptorsmentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

186

135

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Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. Significance of the study This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

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Section: Targeting Nuclear Receptorsmentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

186

135

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“…55 PROTAC molecules contain an ER ligand covalently linked to an E3 ligase, which promotes proteasomal degradation of ER. 55 PROTAC molecules contain an ER ligand covalently linked to an E3 ligase, which promotes proteasomal degradation of ER.…”

Section: Ddpcr Detection Of Esr1 Mutations In Patient Biopsiesmentioning

confidence: 99%

“…Proteolysis targeting chimeras (PROTACs) are being developed to degrade the ER and may prove useful in patients who have ER-positive breast cancer. 55 PROTAC molecules contain an ER ligand covalently linked to an E3 ligase, which promotes proteasomal degradation of ER. Preclinical studies showed that the ER PROTAC ARV-471 promoted potent degradation of ER in multiple ER-positive cell line models.…”

Section: Clinical Implications and Therapeutic Strategies To Treat Mbmentioning

confidence: 99%

ESR1 mutations in breast cancer

Dustin

Fuqua

2019

Cancer

165

131

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The acquisition of ligand-independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)-positive breast cancer is a common mechanism of hormonal therapy resistance. Preclinical and clinical studies have demonstrated that ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis. Several groups have used sensitive detection methods using patient liquid biopsies to track ESR1 or truncal somatic mutations to predict treatment outcome and tumor progression, and some of these techniques may eventually be used to guide sequential treatment options in patients. Further development and standardization of mutation tracking in circulating tumor DNA is ongoing. Clinically, patients with ESR1 mutations derive clinical benefit when treated with fulvestrant and CDK4/6-targeted therapies, but the development of more potent selective ER degraders and/or new targeted biotherapies are needed to overcome the endocrineresistant phenotype of ESR1 mutant-bearing tumors. In this review, we discuss the mechanisms of resistance and dissemination of ESR1 mutations as well as the detection methods for ESR1 mutation tracking, newly discovered potential therapeutic targets, and the clinical implications and treatment options for treating patients with ESR1 mutant-bearing tumors.

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“…Over the past decade, PROTACs have been developed to address an ever-expanding collection of target proteins. Owing to the availability of well-validated chemical matter to repurpose as PROTAC warheads, the majority of early reports focused on degraders of hormone receptors [10][11][12][13], BET-family proteins [14][15][16] and kinases [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. More recently, the applicability of PROTACs has been broadened to include multi-functional proteins (e.g., TRIM24 [34], SMARCA2 [35] tau [36,37]), and HaloTag7-fused proteins for chemical genetics [38].…”

Section: Introductionmentioning

confidence: 99%

Rationalizing PROTAC-mediated ternary complex formation using Rosetta

Bai

Kirubakaran

Karanicolas

2020

Preprint

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PROTACs are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components, then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined.We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation, and that members of a structurally-conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes. Significance StatementRecent years have brought a flood of interest in developing compounds that selectively degrade protein targets in cells, as exemplified by PROTACs. Fully realizing the promise of PROTACs to transform chemical biology by delivering degraders of diverse and undruggable protein targets has been impeded, however, by the fact that designing a suitable chemical linker between the functional moieties requires extensive trial and error. Here, we describe a structure-based computational method to predict PROTAC activity. We envision that this approach will allow design and optimization of PROTACs for efficient target degradation, selection of E3 ligases best suited for pairing with a given target protein, and understanding the basis by which PROTACs can exhibit different target selectivity than their component warheads.

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New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons

Cited by 49 publications

References 33 publications

The PROTAC technology in drug development

The PROTAC technology in drug development

ESR1 mutations in breast cancer

Rationalizing PROTAC-mediated ternary complex formation using Rosetta

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