☆ 4.6 Review

Protein degraders enter the clinic - a new approach to cancer therapy

NATURE REVIEWS CLINICAL ONCOLOGY (2023)

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Article Biochemistry & Molecular Biology

Ligandability of E3 Ligases for Targeted Protein Degradation Applications

Bridget P. Belcher et al.

Summary: Targeted protein degradation using PROTACs and molecular glue degraders is a powerful therapeutic modality for eliminating disease-causing proteins. However, only a small number of E3 ligases have been exploited for this purpose. This review discusses the existing E3 ligases and screening strategies for discovering new E3 ligase recruiters.

BIOCHEMISTRY (2023)

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Article Obstetrics & Gynecology

P253 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER+/human epidermal growth factor receptor 2 (HER2)- breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study

S.A Hurvitz et al.

BREAST (2023)

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Article Oncology

Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis

Arunima Jaiswal et al.

Summary: Resistance to DT2216 is rare in a wide variety of T-ALL cells, and is correlated with decreased degradation of BCL-XL. Resistance to DT2216 in T-ALL is not predicted by initial protein levels. These findings suggest that a phase 2 clinical trial of DT2216 in T-ALL should be widely available, not limited to a subset of patients.

CANCER CHEMOTHERAPY AND PHARMACOLOGY (2023)

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Article Oncology

Recent Advances in the Management of Metastatic Prostate Cancer

Soo Yeon Kim et al.

Summary: The management of metastatic prostate cancer has undergone a revolution with the introduction of new agents and the repurposing of existing ones. These novel therapies have shown improved outcomes and have received approval. The ongoing investigation of multiple new agents is expected to further improve survival outcomes for patients in the coming years.

JCO ONCOLOGY PRACTICE (2022)

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Meeting Abstract Oncology

Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC).

Xin Gao et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Chemistry, Medicinal

Rational Design for Nitroreductase (NTR)-Responsive Proteolysis Targeting Chimeras (PROTACs) Selectively Targeting Tumor Tissues

Shi Shi et al.

Summary: The catalytic properties of PROTACs may cause potential toxicity, but researchers have developed a NTR-responsive PROTAC that can selectively degrade proteins in tumor tissues, thus improving efficacy.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Review Biotechnology & Applied Microbiology

PROTAC targeted protein degraders: the past is prologue

Miklos Bekes et al.

Summary: Targeted protein degradation (TPD) is a new therapeutic modality that can tackle disease-causing proteins which are difficult to target with conventional small molecules. PROTAC molecules, utilizing the ubiquitin-proteasome system to degrade target proteins, has achieved clinical proof-of-concept and attracted significant industry activity. Future directions include identifying target classes suitable for TPD, expanding the use of ubiquitin ligases for precision medicine, and extending the modality beyond oncology.

NATURE REVIEWS DRUG DISCOVERY (2022)

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Meeting Abstract Oncology

First-in-human safety and activity of ARV-471, a novel PROTAC (R) estrogen receptor degrader, in ER+/HER2-locally advanced or metastatic breast cancer

Erika Hamilton et al.

CANCER RESEARCH (2022)

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Review Oncology

Molecular Pathways and Mechanisms of BRAF in Cancer Therapy

Poulikos I. Poulikakos et al.

Summary: This article provides an overview of the progress and limitations in therapeutic strategies targeting activating mutations in BRAF. It discusses the development of newer RAF inhibitors and the need for combination therapies to overcome resistance mechanisms. The article also speculates on the future direction of the field.

CLINICAL CANCER RESEARCH (2022)

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Article Oncology

Phase 1 study of KT-333, a targeted protein degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia, and solid tumors.

Alexander Starodub et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies.

Anthony Mato et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

Phase 1b study of bavdegalutamide, an androgen receptor PROTACdegrader, combined with abiraterone in patients with metastatic prostate cancer.

Neal D. Shore et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

ARV-471, an estrogen receptor (ER) PROTACdegrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2–negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study.

Erika P. Hamilton et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

Phase 1 study of KT-413, a targeted protein degrader, in adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

Don A. Stevens et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Chemistry, Medicinal

Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors

Liwen Hua et al.

Summary: With the successful development of proteolysis-targeting chimeric molecules (PROTACs), the potential of heterobifunctional molecules to contribute to drug design has been recognized. Inspired by PROTACs, various heterobifunctional molecules have been reported to simultaneously bind multiple molecules and bring them into proximity for interaction. This opens up opportunities for advancing drug design by linking potential effectors to a protein of interest (POI).

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Oncology

ASP3082, a First-in-class novel KRAS G12D degrader, exhibits remarkable anti-tumor activity in KRAS G12D mutated cancer models

T. Nagashima et al.

EUROPEAN JOURNAL OF CANCER (2022)

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Article Biochemistry & Molecular Biology

The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells

Alison M. Kurimchak et al.

Summary: Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. However, drug resistance is a substantial challenge in clinical oncology. This study found that resistance to PROTACs can be mediated by the drug efflux pump MDR1. Combination therapies targeting MDR1 may be needed to achieve durable protein degradation and therapeutic response in cancer.

SCIENCE SIGNALING (2022)

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Meeting Abstract Hematology

Kinase Dead BTK Mutations Confer Resistance to Covalent and Noncovalent BTK Inhibitors but Are Susceptible to Clinical Stage BTK Degraders

Skye Montoya et al.

BLOOD (2022)

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Meeting Abstract Hematology

NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton's Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies

Anthony R. Mato et al.

BLOOD (2022)

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Article Chemistry, Medicinal

Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4

Chetan K. Chana et al.

Summary: This study reveals that the GID4 subunit can induce protein degradation. Multiple screening methods identified various binders of GID4, providing candidate scaffolds for developing high-affinity molecules that bind GID4.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Medicinal

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

Yingxu Fang et al.

Summary: Neurodegenerative diseases (NDs) are currently incurable, but the emerging targeted protein degradation (TPD) technologies provide hope for treatment.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Multidisciplinary

Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation

Haixia Liu et al.

Summary: A reactive oxygen species (ROS) triggered leaving group was introduced to parent PROTACs to design and evaluate ROS-responsive Pre-PROTACs, which efficiently degraded the target protein BRD3 according to ROS levels. This research provides an effective approach to control PROTAC activation by the endogenous ROS-related microenvironment.

CHEMICAL COMMUNICATIONS (2022)

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Review Chemistry, Multidisciplinary

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation

Kristin M. Riching et al.

Summary: Targeted protein degradation is a crucial therapeutic approach that requires optimization of multiple parameters to achieve rapid degradation, high potency, and sustained target loss. Degradation is only the first milestone in degrader development, and understanding the dynamic cellular degradation profiles is essential for discovering effective therapeutic agents more efficiently.

CHEMICAL SOCIETY REVIEWS (2022)

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Review Chemistry, Multidisciplinary

Degrader-antibody conjugates

Peter S. Dragovich

Summary: This review provides a current summary of degrader-antibody conjugates (DACs), comparing them with traditional cytotoxic antibody-drug conjugates (ADCs) and highlighting different strategies and challenges associated with DAC generation. The examples demonstrate that biologically-active DACs can be successfully prepared using a variety of PROTAC payloads.

CHEMICAL SOCIETY REVIEWS (2022)

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Review Chemistry, Multidisciplinary

Translational PK-PD for targeted protein degradation

Derek W. Bartlett et al.

Summary: Targeted protein degradation has emerged as an exciting area for therapeutic development in the pharmaceutical industry. This review provides practical insights for understanding the pharmacokinetic and pharmacodynamic properties of protein degraders, and offers a roadmap for their translational development. By using quantitative mathematical frameworks and standard experimental assays, this review highlights the unique characteristics of protein degraders and their potential in drug development.

CHEMICAL SOCIETY REVIEWS (2022)

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Article Pharmacology & Pharmacy

A kinetic proofreading model for bispecific protein degraders

Derek W. Bartlett et al.

Summary: The study describes a mechanistic modeling framework for bispecific protein degraders (BPDs) that involves ternary complex formation and degradation via the ubiquitin-proteasome system. A multi-step process in the model results in a time delay, balancing ternary complex stability and proteasome degradation rates. This concept applies kinetic proofreading in a quantitative pharmacokinetic-pharmacodynamic framework to inform the design of potent and selective BPDs.

JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS (2021)

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Article Oncology

Targeting pan-essential genes in cancer: Challenges and opportunities

Liang Chang et al.

Summary: Despite significant successes in clinical settings, the development of cancer targeted therapy remains challenging, with a disappointingly high failure rate. The misapplication of the targeted therapy paradigm to therapeutics targeting pan-essential genes is a key factor contributing to this issue. Strategies to avoid previous pitfalls and support the ongoing and future development of pan-essential therapeutics are suggested.

CANCER CELL (2021)

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Meeting Abstract Hematology

Nx-5948, a Selective Degrader of BTK with Activity in Preclinical Models of Hematologic and Brain Malignancies

Daniel W. Robbins et al.

BLOOD (2021)

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Meeting Abstract Hematology

A First-in-Class STAT3 Degrader KT-333 in Development for Treatment of Hematologic Cancers

Phillip C. C. Liu et al.

BLOOD (2021)

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Review Biochemistry & Molecular Biology

Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors

Georgia Gomatou et al.

Summary: CDK 4/6 inhibitors have shown promise in treating breast cancer, but patients often develop resistance. Studies indicate that resistance mechanisms involve aberrations of cell cycle molecules and rewiring of the cell to reduce dependence on CDK 4/6.

MOLECULAR BIOLOGY REPORTS (2021)

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Article Biochemistry & Molecular Biology

Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes

James Schiemer et al.

Summary: Heterobifunctional chimeric degraders are ligands that recruit target proteins to E3 ubiquitin ligases to induce protein degradation. This study characterized degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1 using biochemical, biophysical and structural studies, revealing new insights and showing that increased ternary complex stability or rigidity does not always correlate with increased degradation efficiency.

NATURE CHEMICAL BIOLOGY (2021)

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Article Cell Biology

Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins

Ryosuke Shirasaki et al.

Summary: The resistance mechanisms to degraders targeting different oncoproteins are mainly due to prevention, rather than adaptation, of the breakdown of target oncoproteins, which is possibly caused by the loss of function of the cognate E3 ligase or its interactors/regulators.

CELL REPORTS (2021)

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Article Chemistry, Medicinal

Integrative Modeling of PROTAC-Mediated Ternary Complexes

Gaoqi Weng et al.

Summary: Proteolysis-targeting chimeras (PROTACs) represent an emerging drug discovery technology that selectively induce targeted protein degradation. PROTAC-Model, an integrative computational method, was developed to predict PROTAC-mediated ternary complex structures and showed better performance in rational design of PROTACs.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Review Biochemistry & Molecular Biology

The Development of BTK Inhibitors: A Five-Year Update

Bruno Tasso et al.

Summary: BTK has been a significant target for therapeutic agents in cancer and autoimmune disorders, with both irreversible and reversible inhibitors being developed and investigated. Research on BTK function and inhibitors is of interest for pharmaceutical companies and academia.

MOLECULES (2021)

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Article Chemistry, Medicinal

Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta

Nan Bai et al.

Summary: PROTACs are molecules that induce target protein degradation by combining a target-binding warhead with an E3 ligase-recruiting moiety. A structure-based computational method has been developed to evaluate the suitability of linkers for ternary complex formation, which can explain PROTACs' activity and selectivity. Modeling ternary complex formation can help interpret PROTAC activity and reveal different binding modes within structurally conserved protein families.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2021)

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Article Multidisciplinary Sciences

Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells

Ryan Kolb et al.

Summary: The pharmacological degradation of BCL-X-L preferentially induces apoptosis of tumor-infiltrating Tregs, promoting CD8 T cell activation and effective suppression of tumor growth without causing damage to normal tissues or thrombocytopenia. This finding suggests that targeting BCL-X-L could be a potential therapeutic strategy for cancer immunotherapy.

NATURE COMMUNICATIONS (2021)

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Article Chemistry, Medicinal

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Alesa Bricelj et al.

Summary: The attachment points of CRBN ligands have a significant impact on their stability and degradation features, providing a blueprint for the development of future CRBN-based degraders with tailored properties.

ACS MEDICINAL CHEMISTRY LETTERS (2021)

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Article Chemistry, Medicinal

Bispecific Estrogen Receptor a Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening

Jeremy S. Disch et al.

Summary: The research identified novel bispecific degrader leads from DECL screening, with the off-DNA synthesized small molecule exemplar 7 showing nanomolar ER alpha binding, antagonism, and degradation. This approach paves the way for further exploration in developing bispecific degraders of ER alpha with improved efficacy.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Multidisciplinary

Cancer Selective Target Degradation by Folate-Caged PROTACs

Jing Liu et al.

Summary: PROTACs are emerging as a promising therapeutic modality for degrading intracellular protein targets, but potential toxicity in normal cells limits their applications. By conjugating a folate group to a ligand of the VHL E3 ubiquitin ligase, a cancer cell selective delivery strategy for PROTACs was developed to achieve targeted degradation of proteins of interest in cancer cells. Folate-PROTACs provide a platform for selective degradation of proteins of interest in cancer cells.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2021)

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Article Chemistry, Medicinal

SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression

Haibin Zhou et al.

Summary: SD-91 is a potent, highly selective, and efficacious STAT3 degrader that effectively induces degradation of STAT3 protein with high selectivity, demonstrating complete and long-lasting tumor regression in preclinical models. It has the potential for extensive evaluations in the treatment of human cancers and diseases where STAT3 plays a critical role.

ACS MEDICINAL CHEMISTRY LETTERS (2021)

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Editorial Material Biochemistry & Molecular Biology

Novel Mechanisms of Molecular Glue-Induced Protein Degradation

Shanique Alabi

BIOCHEMISTRY (2021)

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Review Hematology

Resistance to Bruton tyrosine kinase inhibitors: the Achilles heel of their success story in lymphoid malignancies

Deborah M. Stephens et al.

Summary: BTK inhibitors have revolutionized the treatment of B-cell malignancies, but resistance remains a challenge. Identifying clinical and molecular risk factors can help predict patients at highest risk for developing BTKi resistance, while the introduction of drugs like Venetoclax has shown promise in extending survival for these patients. Ongoing clinical trials with novel treatments, such as next-generation BTK inhibitors and CAR T-cell therapy, are showing efficacy in patients with BTKi-resistant disease. Continued research on resistance mechanisms is crucial for improving outcomes in this patient population.

BLOOD (2021)

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Article Chemistry, Medicinal

Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

Weiguo Xiang et al.

Summary: This study identifies a promising AR degrader for the treatment of advanced prostate cancer, which demonstrates potent inhibition in cell lines with AR gene amplification or mutations and shows good oral bioavailability in mice.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras

He Chen et al.

Summary: This study presents a general strategy for delivering IMiD-based molecular glues and PROTACs to FOLR1-expressing cancer cells, effectively degrading fusion proteins in cancer cells with the potential to ameliorate toxicity.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Xin Han et al.

Summary: This study outlines strategies for discovering highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics, successfully identifying compound ARD-2128 as the most effective in inhibiting tumor growth in mice with good oral bioavailability.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Optimization of a Series of RIPK2 PROTACs

Afjal H. Miah et al.

Summary: This study optimized a series of RIPK2 PROTACs through reducing the lipophilicity of the lead compound, leading to improved solubility and stability. Effective RIPK2 PROTACs with attractive pharmacokinetic profiles were successfully developed, along with the feasibility of a long-acting parenteral formulation demonstrated.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

Troy A. Bemis et al.

Summary: A current bottleneck in the development of PROTACs is the empirical nature of linker length structure-activity relationships. A multi-disciplinary approach has been detailed to alleviate this bottleneck. Research has focused on synthetic approaches to increase throughput, advances in structural biology and computational chemistry for rational PROTAC design, and de novo linker design in silico.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Review Biochemistry & Molecular Biology

Optical control of targeted protein degradation

Martin Reynders et al.

Summary: Light-responsive degraders are emerging as small-molecule tools that can control protein degradation using light, showing potential for precision medicine applications.

CELL CHEMICAL BIOLOGY (2021)

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Review Biochemistry & Molecular Biology

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Lei Zhong et al.

Summary: Targeted therapeutic drugs have become mainstream cancer treatments due to their advantages in efficacy and safety, but still face challenges such as low response rate and drug resistance. A comprehensive review was conducted on small-molecule targeted anti-cancer drugs to promote their development, discussing current challenges and providing insights and perspectives for future research and development.

SIGNAL TRANSDUCTION AND TARGETED THERAPY (2021)

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Article Biochemical Research Methods

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

Tasuku Ishida et al.

Summary: PROTACs, or bifunctional degrader molecules, are a novel approach for understanding and treating human diseases by targeting specific proteins for degradation. Advances in nonpeptidic small-molecule E3 ligase ligands, such as VHL and CRBN, have revolutionized the field and led to the development of drug-like PROTACs with powerful degradation capabilities. Ongoing research aims to expand the chemical diversity of PROTACs and explore new approaches for targeted protein degradation.

SLAS DISCOVERY (2021)

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Review Oncology

Response and Resistance to BCR-ABL1-Targeted Therapies

Theodore P. Braun et al.

CANCER CELL (2020)

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Review Oncology

Overcoming Endocrine Resistance in Breast Cancer

Ariella B. Hanker et al.

CANCER CELL (2020)

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Article Medicine, General & Internal

Small molecules, big impact: 20 years of targeted therapy in oncology

Philippe L Bedard et al.

LANCET (2020)

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Review Pharmacology & Pharmacy

Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective

Andy Pike et al.

DRUG DISCOVERY TODAY (2020)

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Article Chemistry, Multidisciplinary

Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs

Michael J. Bond et al.

ACS CENTRAL SCIENCE (2020)

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Article Oncology

DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

Yonghan He et al.

JOURNAL OF HEMATOLOGY & ONCOLOGY (2020)

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Article Chemistry, Medicinal

PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes

Daniel Zaidman et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2020)

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Article Chemistry, Medicinal

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies

Michael L. Drummond et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2020)

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Article Chemistry, Medicinal

Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase

Sebastien L. Degorce et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Article Chemistry, Medicinal

Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications

Laura Goracci et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Review Oncology

Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia

Melat T. Gebru et al.

JOURNAL OF HEMATOLOGY & ONCOLOGY (2020)

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Review Medicine, General & Internal

Systemic Therapy for Estrogen Receptor-Positive, HER2-Negative Breast Cancer

Harold J. Burstein

NEW ENGLAND JOURNAL OF MEDICINE (2020)

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Meeting Abstract Hematology

Ktx-120, a Novel Irakimid Degrader of IRAK4 and IMiD Substrates Shows Preferential Activity and Induces Regressions in MYD88-Mutant DLBCL CDX and PDX Models

Duncan Walker et al.

BLOOD (2020)

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Meeting Abstract Hematology

Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies

Daniel W. Robbins et al.

BLOOD (2020)

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Article Biology

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Alina Mares et al.

COMMUNICATIONS BIOLOGY (2020)

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Article Chemistry, Multidisciplinary

Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6

Baishan Jiang et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2019)

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Meeting Abstract Oncology

ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer.

Taavi Neklesa et al.

JOURNAL OF CLINICAL ONCOLOGY (2019)

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Review Oncology

Regulatory T cells in cancer immunosuppression - implications for anticancer therapy

Yosuke Togashi et al.

NATURE REVIEWS CLINICAL ONCOLOGY (2019)

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Article Oncology

Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 Ligase Complexes

Lu Zhang et al.

MOLECULAR CANCER THERAPEUTICS (2019)

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Review Chemistry, Medicinal

Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges

Scott D. Edmondson et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2019)

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Article Oncology

Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation

George M. Burslem et al.

CANCER RESEARCH (2019)

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Article Biochemistry & Molecular Biology

BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design

William Farnaby et al.

NATURE CHEMICAL BIOLOGY (2019)

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Article Biochemistry & Molecular Biology

Plasticity of the Cullin-RING Ligase Repertoire Shapes Sensitivity to Ligand-Induced Protein Degradation

Cristina Mayor-Ruiz et al.

MOLECULAR CELL (2019)

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Article Biochemistry & Molecular Biology

A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity

Sajid Khan et al.

NATURE MEDICINE (2019)

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Article Multidisciplinary Sciences

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase

Blake E. Smith et al.

NATURE COMMUNICATIONS (2019)

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Meeting Abstract Oncology

ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer

J. J. Flanagan et al.

CANCER RESEARCH (2019)

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Article Chemistry, Medicinal

Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection

David A. DeGoey et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Biochemistry & Molecular Biology

Targeting the C481S Ibrutinib-Resistance Mutation in Bruton's Tyrosine Kinase Using PROTAC-Mediated Degradation

Alexandru D. Buhimschi et al.

BIOCHEMISTRY (2018)

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Article Biochemistry & Molecular Biology

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

David A. Quigley et al.

CELL (2018)

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Article Biochemistry & Molecular Biology

A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer

David Y. Takeda et al.

CELL (2018)

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Review Biochemistry & Molecular Biology

Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space

Vasanthanathan Poongavanam et al.

CURRENT OPINION IN CHEMICAL BIOLOGY (2018)

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Plasticity in binding confers selectivity in ligand-induced protein degradation

Radoslaw P. Nowak et al.

NATURE CHEMICAL BIOLOGY (2018)

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Review Oncology

NTRK fusion-positive cancers and TRK inhibitor therapy

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NATURE REVIEWS CLINICAL ONCOLOGY (2018)

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Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

Gerard L. Brien et al.

ELIFE (2018)

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Article Biochemistry & Molecular Biology

Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead

Daniel P. Bondeson et al.

CELL CHEMICAL BIOLOGY (2018)

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Review Biotechnology & Applied Microbiology

DNA-encoded chemistry: enabling the deeper sampling of chemical space

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NATURE REVIEWS DRUG DISCOVERY (2017)

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Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists

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CANCER DISCOVERY (2017)

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Structural basis of PROTAC cooperative recognition for selective protein degradation

Morgan S. Gadd et al.

NATURE CHEMICAL BIOLOGY (2017)

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Review Pharmacology & Pharmacy

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ENDOCRINE CONNECTIONS (2017)

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Understanding and targeting resistance mechanisms in NSCLC

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NATURE REVIEWS CANCER (2017)

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Review Biochemistry & Molecular Biology

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Philipp M. Cromm et al.

CELL CHEMICAL BIOLOGY (2017)

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Review Oncology

A Review of Fulvestrant in Breast Cancer

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ONCOLOGY AND THERAPY (2017)

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Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer

Alexander W. Wyatt et al.

JAMA ONCOLOGY (2016)

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Article Biotechnology & Applied Microbiology

Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

Nada Lallous et al.

GENOME BIOLOGY (2016)

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Article Biochemistry & Molecular Biology

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of Halo Tag Fusion Proteins

Dennis L. Buckley et al.

ACS CHEMICAL BIOLOGY (2015)

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Article Biochemistry & Molecular Biology

Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

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ACS CHEMICAL BIOLOGY (2015)

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Integrative Clinical Genomics of Advanced Prostate Cancer

Dan Robinson et al.

CELL (2015)

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Article Biochemistry & Molecular Biology

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4

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CHEMISTRY & BIOLOGY (2015)

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Article Oncology

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer

Arun A. Azad et al.

CLINICAL CANCER RESEARCH (2015)

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Article Biochemistry & Molecular Biology

Catalytic in vivo protein knockdown by small-molecule PROTACs

Daniel P. Bondeson et al.

NATURE CHEMICAL BIOLOGY (2015)

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Phthalimide conjugation as a strategy for in vivo target protein degradation

Georg E. Winter et al.

SCIENCE (2015)

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Plasma AR and abiraterone-resistant prostate cancer

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SCIENCE TRANSLATIONAL MEDICINE (2015)

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Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies

Christine M. Lovly et al.

CLINICAL CANCER RESEARCH (2014)

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Article Chemistry, Medicinal

Structure-Guided Design and Optimization of Small Molecules Targeting the Protein Protein Interaction between the von Hippel- Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities

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JOURNAL OF MEDICINAL CHEMISTRY (2014)

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Determining the optimal dose in the development of anticancer agents

Ron H. J. Mathijssen et al.

NATURE REVIEWS CLINICAL ONCOLOGY (2014)

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Review Cell Biology

Perilous journey: a tour of the ubiquitin-proteasome system

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TRENDS IN CELL BIOLOGY (2014)

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A Comprehensive Mathematical Model for Three-Body Binding Equilibria

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2013)

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A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer

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BREAST CANCER RESEARCH (2013)

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Article Chemistry, Multidisciplinary

Small-Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1a

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ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2012)

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Review Biochemistry & Molecular Biology

The Ubiquitin Code

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ANNUAL REVIEW OF BIOCHEMISTRY, VOL 81 (2012)

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Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

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BREAST CANCER RESEARCH AND TREATMENT (2012)

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A Comprehensive Survey of Ras Mutations in Cancer

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CANCER RESEARCH (2012)

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Protein Knockdown Using Methyl Bestatin-Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2010)

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Identification of a Primary Target of Thalidomide Teratogenicity

Takumi Ito et al.

SCIENCE (2010)

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Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics

Ashley R. Schneekloth et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2008)

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JOURNAL OF BIOSCIENCES (2006)

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Drug therapy: Imatinib mesylate - A new oral targeted therapy.

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NEW ENGLAND JOURNAL OF MEDICINE (2002)

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Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2001)

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