Proteolysis Targeting Chimera Technology Research Articles

Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation.MethodsThis study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo.ResultsThrough the design, synthesis and screening of a series of targeted compounds, we identified YZ-836P as an effective compound that exerted cytotoxic effects and reduced the protein levels of PRMT5 and its key downstream target protein KLF5 in TNBC after 48 h. Its efficacy was significantly superior to the PRMT5 PROTAC degraders that had been reported. YZ-836P induced G1 phase cell cycle arrest and significantly induced apoptosis in TNBC cells. Additionally, we demonstrated that YZ-836P promoted the ubiquitination and degradation of PRMT5 in a cereblon (CRBN)-dependent manner. Notably, YZ-836P exhibited pronounced efficacy in inhibiting the growth of TNBC patient-derived organoids and xenografts in nude mice.ConclusionsThese findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC.Trial registrationEthics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023.

PROTAC and Molecular Glue Degraders of the Oncogenic RNA Binding Protein Lin28.

The interaction between proteins and RNA is crucial for regulating gene expression, with dysregulation often linked to diseases such as cancer. The RNA-binding protein (RBP) Lin28 inhibits the tumor suppressor microRNA (miRNA)let-7, making it a significant oncogenic factor in tumor progression and metastasis. In this study, a small molecule is used that binds Lin28 and blocks its inhibition of let-7. To enhance its efficay, the inhibitor is transformed into degraders via two degradation approaches: Proteolysis Targeting Chimera (PROTAC) and molecular glue. A series of PROTAC bifunctional molecules and molecular glues capable of degrading Lin28 in cells.is developed Both strategies significantly reduce overexpressed Lin28 and alleviate cancer cellular phenotypes. Notably, the molecular glue approach demonstrates exceptional potency, surpassing PROTAC in several aspects. This outcome underscores the superior efficiency of the molecular glue approach for targeted Lin28 degradation and highlights its potential for addressing associated diseases with small molecules. Innovative small molecule strategies such as molecular glue and PROTAC technology for targeted RBP degradation, hold promise for opening new avenues in RNA modulation and addressing related diseases.

Integral Membrane Protein Degradation: A Novel Paradigm by PROTAC Technology

: Integral membrane proteins are attractive targets for therapeutic intervention due to their crucial roles in cellular functions and their involvement in various diseases. However, targeting these proteins for degradation has posed significant challenges due to their complex structures and diverse functions. The emergence of proteolysis-targeting chimeras (PROTAC) represents a groundbreaking paradigm shift in drug development, offering a novel approach to address the degradation of integral membrane proteins. This review explores the innovative application of PROTAC technology in inducing the degradation of integral membrane proteins. PROTACs are molecules that have two roles: they bring together specific target proteins and E3 ubiquitin ligases, which help with ubiquitination and the degradation of proteins by proteasomes. As PROTACs are made up of separate parts, they can be put together to make custom molecules that can target difficult targets, such as integral membrane proteins. This review covers recent developments and advancements in the design and optimisation of PROTACs tailored for integral membrane protein degradation. Furthermore, it also discusses the problems that come up when trying to target membrane proteins and how PROTACs solve these problems by using ligands that can pass cell membranes and specifically interact with target proteins. It delves into the potential therapeutic implications of degrading integral membrane proteins using PROTACs and elucidates the impact of this novel approach in treating diseases that involve aberrant membrane protein expression or function by highlighting specific examples and case studies.

Unlocking Cellular Control: The Promise of PROTACs in Disease Intervention

The discovery of proteolysis-targeting chimeras (PROTACs)[6] is among the most exciting and promising avenues in cancer therapy. [14] These fascinating compounds signify a paradigm shift from traditional approaches to medication development, offering a new idea that leverages the complexities of biological mechanisms to accomplish highly focused degradation of particular proteins implicated in pathological processes.[16] This novel strategy has the potential to address a number of drawbacks with conventional therapy techniques, such as the development of drug resistance and unexpected adverse effects resulting from interactions that are not intended. [14] The fundamental attraction of PROTACs is their distinct mode of action, which is based on controlling the cell's own machinery for protein degradation.[11] This orchestrated degradation translates to a substantial reduction in the levels of disease-driving proteins, often leading to the disruption of critical pathways involved in cancer growth and progression.[9] The in-depth principles underlying PROTAC technology are thoroughly explored in this review study, which also provides insight into the complex chemical mechanisms that enable these chimeric molecules to specifically degrade certain proteins while leaving others intact. Showcasing the potential of PROTACs as a revolutionary force in targeted cancer therapy, and focusing on its application in prostate and breast cancer especially, the article draws from a comprehensive compilation of preclinical and clinical studies, advancements, and breakthroughs in the field. [10] The methods used to create and refine PROTACs for various cancer types will be examined throughout the review, along with the subtleties of the ligand and linker choices that are crucial to their effectiveness and selectivity.[6] The difficulties and possibilities of transferring this ground-breaking technology from the lab to clinical practice will also be thoroughly examined, with an emphasis on issues like bioavailability, administration strategies, and potential resistance mechanisms.[9] Through the integration of perspectives from various studies, the objective is to present a thorough but succinct review of the state of ongoing PROTAC research, emphasizing both, noteworthy advancements and the important issues that still need to be resolved. In the end, our investigation into PROTACs aims to shed light on how they can change the face of cancer therapy by providing a preview of a day when targeted protein degradation of disease-causing proteins would lead the way in novel therapeutic approaches.[9]

Ultrasound Controllable Release of Proteolysis Targeting Chimeras for Triple-Negative Breast Cancer Treatment.

Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, which is highly aggressive and incurable. Here, we proposed an ultrasound activatable bromodomain-containing protein 4 (BRD4) proteolysis targeting chimera (PROTAC) release strategy for the first time for precisely controlled protein degradation in preclinical TNBC model. Through combination of PROTAC and ultrasound-targeted microbubble destruction (UTMD) technology, the present strategy also aims to concurrently solve the major limitations of poor loading capacity of microbubbles and undesirable targeting and membrane permeability of PROTAC. PROTAC (ARV-825)-encapsulated microbubbles, ARV-MBs, were developed for the efficacious treatment of TNBC invitro and invivo. The microbubbles we synthesized showed ultrasound-responsive drug release ability, which could effectively promote the penetration of PROTAC into tumor site and tumor cell. Under ultrasound, ARV-MBs could play an effective antitumor effect by potentiating the ubiquitination and degradation of BRD4 in tumor. The current study may provide a new idea for promoting clinical translation of drug-loaded microbubbles and PROTAC, and offer a new efficacious therapeutic modality for TNBC.

PROteolysis Targeting Chimeras: A new cutting‐edge nanomedicine for colorectal cancer

AbstractColorectal cancer (CRC) is a prevalent malignancy with a high mortality rate, necessitating innovative treatment strategies. PROTACs (PROteolysis Targeting Chimeras) represent a promising therapeutic approach by targeting and degrading oncogenic proteins via the ubiquitin‐proteasome pathway. This study explores the potential of using exosomes as delivery vehicles for PROTACs to enhance treatment efficacy. Exosomes, due to their biocompatibility and inherent targeting capabilities, offer a precise method for delivering PROTACs to CRC cells, potentially overcoming challenges associated with traditional therapies such as drug resistance and off‐target effects. By harnessing the advantages of both exosome‐based delivery and PROTAC technology, this approach aims to improve targeted protein degradation and therapeutic outcomes in CRC treatment. Further research is required to optimize exosome engineering, ensure efficient PROTAC loading, and validate the safety and efficacy of this novel therapeutic strategy through preclinical and clinical trials.

Development of novel antivrial agents that induce the degradation of the main protease of human-infecting coronaviruses

The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (Mpro), a conserved enzyme essential for viral replication and pathogenicity. By adapting the Mpro inhibitor GC376, we produced two novel PROTACs, P2 and P3, which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 μM, and neither showed cytotoxicity at 100 μM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading Mpro within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs.

Targeting the Interplay of Proteins through PROTACs for Management Cancer and Associated Disorders

Abstract: Cancer remains a formidable global health challenge, necessitating innovative therapeutic strategies. Traditional small-molecule inhibitors often face limitations in selectively targeting diseaseassociated proteins, leading to side effects and incomplete therapeutic responses. Proteolysistargeting chimeras (PROTACs) turned out to be a promising approach to address these challenges. Unlike traditional inhibitors, PROTACs leverage the cellular ubiquitin-proteasome system to selectively degrade disease-associated proteins. In this review, we addressed PROTACs: Targeted approach for cancer management, key findings, limitations, and future perspectives. For this, the authors have critically reviewed literature obtained from prime sources comprising Google Scholar, Web of Science, PubMed, and Publons. From the selected papers' reference section, a number of pertinent articles were retrieved. Preclinical studies and early-phase clinical trials have demonstrated the efficacy and potential of PROTACs in cancer management. Additionally, the potential of PROTACs in overcoming therapy resistance, tackling tumor heterogeneity, and engaging multiple pathways is explored. As research advances, addressing challenges and refining PROTAC technology will pave the way for their integration into the next generation of cancer therapeutics, marking a transformative era in precision medicine.

Targeted Protein Degradation Technology: A Novel Strategy for Cancer Therapy

PROteolysis TArgeting Chimera (PROTAC) technology is an effective tool to induce targeted degradation of pathogenic protein and is a novel cancer therapy. It uses the endogenous ubiquitin‐protease system (UPS), attracting ubiquitin and covering the target protein in it, thus resulting in its complete degradation of the protein interest (POI). The potential advantages of PROTAC technology compensate for the shortcomings of traditional cancer therapy and allow them to target “undruggable” proteins, which promote its rapid development in recent years. The review focuses on the mechanisms of PROTACs, discusses application of PROTACs targeting different oncogenic proteins and analyzes the strategies for designing efficient PROTACs. Collectively, the review provides references for future application of PROTACs in cancer treatment.

Fluorescence theranostic PROTACs for real-time visualization of ERα degradation

Proteolysis targeting chimera (PROTAC) technology, a groundbreaking strategy for degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. However, the real-time monitoring and visualization of protein degradation processes have been long-standing challenges in the realm of drug development. In this research, we sought to amalgamate the highly efficient protein-degrading capabilities of PROTAC technology with the visualization attributes of fluorescent probes, with the potential to pave the path for the design and development of a novel class of visual PROTACs. These novel PROTACs uniquely possess both fluorescence imaging and therapeutic characteristics, all with the goal of enabling real-time observations of protein degradation processes. Our approach involved the utilization of a high ER-targeting fluorescent probe, previously reported in our laboratory, which served as a warhead that specifically binds to the protein of interest (POI). Additionally, a VHL ligand for recruiting E3 ligase and linkers of various lengths were incorporated to synthesize a series of novel ER-inherent fluorescence PROTACs. Among them, compound A3 demonstrated remarkable efficiency in degrading ERα proteins (DC50 = 0.12 μM) and displaying exceptional anti-proliferative activity against MCF-7 cells (IC50 = 0.051 μM). Furthermore, it exhibited impressive fluorescence imaging performance, boasting an emission wavelength of up to 582 nm, a Stokes shift of 116 nm, and consistent optical properties. These attributes make it especially suitable for the real-time, in situ tracking of ERα protein degradation processes, thus may serve as a privileged visual theranostic PROTAC for ERα+ breast cancer. This study not only broadens the application spectrum of PROTAC technology but also introduces a novel approach for real-time visualization of protein degradation processes, ultimately enhancing the diagnostic and treatment efficacy of PROTACs.

Harnessing PROTAC technology to combat stress hormone receptor activation

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential.

Discovery of proteolysis-targeting chimera targeting undruggable proteins using a covalent ligand screening approach

Targeted protein degradation (TPD) technology, such as proteolysis-targeting chimera (PROTAC), has become a new therapeutic modality. However, the degradation of undruggable proteins, such as those involved in protein-protein interactions (PPIs), using PROTAC is still limited owing to the difficulties in finding small-molecule binders of these proteins. To identify new chemical moieties that bind to the target sites of the protein of interest (POI), we conducted a site-specific and fragment-based covalent ligand screening using liquid chromatography-tandem mass spectrometry (LC-MS/MS). To apply the selected hits to the PROTAC approach, two-dimensional (2D) nuclear magnetic resonance (NMR) experiments were performed to evaluate the reversible binding of their analogs without covalent warheads. To proof the proposed approach, human mouse double minute (MDM)2 was selected as a model system since it is involved in PPIs and is known to be a degradable target protein. Western blot analysis showed that newly synthesized PROTACs, incorporated reversible analogs of screening hits, affected degradation in a dose- and time-dependent manner. This methodology makes it possible to use PROTAC technology to exploit previously undruggable proteins for TPD.

Development of decoy oligonucleotide-warheaded chimeric molecules targeting STAT3

Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in the drug development community, and over 20 PROTAC molecules are currently under clinical evaluation. These PROTAC molecules contain small-molecule warheads that bind to target proteins. Recently, oligonucleotide-warheaded PROTACs have emerged as a promising new tool to degrade DNA-binding proteins such as transcription factors. In this study, we applied an oligonucleotide-warheaded PROTAC technology to induce the degradation of signal transducer and activator of transcription 3 (STAT3), which is a hard-to-target protein. A double-stranded decoy oligonucleotide specific to STAT3 was conjugated to E3 binders (pomalidomide, VH032, and LCL161) to generate PROTAC molecules that recruited different E3 ubiquitin ligases cereblon (CRBN), von Hippel-Lindau (VHL), and inhibitor of apoptosis protein (IAP), respectively. One of the resulting PROTAC molecules, POM-STAT3, which recruits CRBN, potently induces STAT3 degradation. STAT3 degradation by POM-STAT3 was abolished by scrambling the oligonucleotide sequences of POM-STAT3 and by adding a double-stranded decoy oligonucleotide against STAT3 in a competitive manner, suggesting the significance of oligonucleotide sequences in STAT3 degradation. Moreover, POM-STAT3-induced STAT3 degradation was suppressed by the CRBN binder thalidomide, proteasome inhibitor bortezomib, E1 inhibitor MLN7243, and siRNA-mediated depletion of CRBN, indicating that STAT3 degradation is mediated by the ubiquitin-proteasome system, which involves CRBN as the responsible E3 ubiquitin ligase. Consistent with STAT3 degradation, NCI-H2087 cell viability was severely reduced following POM-STAT3 treatment. Thus, POM-STAT3 is a STAT3 degrader that potentially has cytocidal activity against cancer cells that are highly dependent on STAT3 signaling, which implies that inducing protein degradation by decoy oligonucleotide-warheaded PROTAC molecules could be harnessed to be therapeutic against oncogenic transcription factors.

PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders

IntroductionNatural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. ObjectivesInspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. MethodsTaking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. ResultsIn this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10-hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo, leading to potent antitumor activities and reduced toxic side effects. ConclusionIn summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development.

Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient Degraders of Extracellular Signal-Regulated Kinase 5.

Extracellular signal-regulated kinase 5 (ERK5) is recognized as a key member of the mitogen-activated protein kinase family and is involved in tumor growth, migration, and angiogenesis. However, the results of ERK5 inhibition in multiple studies are controversial, and a highly specific ERK5-targeting agent is required to confirm physiological functions. Using proteolysis-targeting chimera technology, we designed the selective ERK5 degrader PPM-3 and examined its biological effect on cancer cells. Interestingly, the selective degradation of ERK5 with PPM-3 did not influence tumor cell growth directly. Based on proteomics analysis, the ERK5 deletion may be associated with tumor immunity. PPM-3 influences tumor development by affecting the differentiation of macrophages. Therefore, PPM-3 is an effective small-molecule tool for studying ERK5 and a promising immunotherapy drug candidate.

WITHDRAWN: Targeted protein degradation: A promising approach for cancer treatment

Targeted protein degradation (TPD) is a promising approach that has the ability to address disease-causing proteins. Compared to traditional inhibition, proteolysis targeting chimera (PROTAC) technology offers various benefits, including the potential to target mutant and overexpressed proteins along with characteristics to target undruggable proteomes. A significant obstacle to the ongoing effective treatment of malignancies is cancer drug resistance, which is developed frequently by mutated or overexpressed protein targets and causes current remedies to continuously lose their effectiveness. The effective use of PROTACs to degrade targets that have undergone mutations and conferred resistance to first-line cancer therapies has attracted much research attention. To find novel/effective treatments, we analyzed the advancements in PROTACs aimed at cancer resistance and targets. This review provides a description of how PROTAC-based anticancer drugs are currently being developed and how to counter resistance if developed to PROTAC technology. Moreover, modern technologies related to protein degradation, including autophagy-targeting chimeras (AUTAC), lysosome-targeting chimeras (LYTAC), antibody-based PROTAC (AbTAC), Glue-body chimeras (GlueTAC), transcription-factor-targeting chimeras (TRAFTAC), RNA-PROTAC, aptamer-PROTAC, Photo-PROTAC, folate-PROTAC, and in-cell click-formed proteolysis targeting chimeras (CLIPTACs), have been discussed along with their mechanisms of action.

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library.

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.

The role and efficacy of PROTAC in FLT3-mutated AML treatment

Small molecule Proteolysis Targeting Chimera (PROTAC) is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML). By activating the ubiquitination system, PROTAC can generate protein and kinase degradation upon FLT3 to perform outcomes of antiproliferative activities. The focus of this study revolves around the investigation of the efficacy of VHL and CRBN-based PROTAC on FLT3 degradation compared to conventional immunotherapy agents such as quizartinib. By assessing the performances of PROTAC on MOLM-14 and MV4-11 cells with other therapies, comparing both adverse effects and benefits could demonstrate crucial approaches to applying PROTAC for AML treatments. The VHL-recruiting PROTAC based on the modification of quizartinib has shown promising effects where FLT3 within MV4-11 injected athymic mice had experienced around a 60% of decrease. The CRBN-based degrader TL12-186, on the other hand, had also demonstrated antiproliferative outcomes where 14 out of 7559 proteins of the MOLM-14 cell have been successfully degraded, showing a more than 25% decrease. Even though there seem to be some improvements in the VHL-recruiting PROTAC compared to traditional immunotherapy agents like quizartinib, CRBN-mediated PROTAC has shown a relatively less significant result. Critiquing in a variety of aspects, quizartinib has demonstrated better performance in cell permeability, low nanomolecular concentration, and degradation. The significance of this study provides an overview of existing PROTAC technology that shows effects on the treatment of FLT3-mutated AML. Further studies may be conducted on the foundation of this study to demonstrate the enhancements of each modified PROTAC compared to existing therapies.

The next generation of EGFR inhibitors: a patenting perspective of PROTACs based EGFR degraders

ABSTRACT Introduction Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials. Areas covered This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs. Expert opinion By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.

Clinician's guide to targeted estrogen receptor degradation using PROTAC in patients with estrogen receptor-positive metastatic breast cancer.

Metastatic breast cancer (MBC) remains a major clinical challenge, necessitating the development of innovative therapeutic strategies. Estrogen receptor (ER) degradation using proteolysis-targeting chimeras (PROTAC) has emerged as a promising approach for overcoming acquired resistance to endocrine therapy. This review will summarize recent findings, highlighting the role of ER degradation by PROTAC in patients with MBC. The application of PROTAC technology for ER degradation has demonstrated initial success in preclinical and early clinical studies. PROTACs, consisting of an ER-targeting moiety, an E3 ubiquitin ligase-recruiting moiety, and a linker, facilitate ER ubiquitination and subsequent proteasomal degradation. Yet, significant challenges persist in the clinical translation of ER degradation by PROTAC. These include the optimization of PROTAC design, elucidation of mechanisms underlying resistance to PROTAC-induced ER degradation, and identification of predictive biomarkers for patient stratification. Additionally, addressing potential off-target effects and toxicity profiles remains a critical aspect of developing PROTAC-based therapies. Recent data demonstrate the potential of ER degradation by PROTAC as a therapeutic strategy for patients with MBC. Continued research efforts and development of synergistic combinations are crucial for further advancing PROTAC-based therapies and improving outcomes in patients with MBC.