4.7 Article

Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins

Related references

Note: Only part of the references are listed.
Article Chemistry, Medicinal

Discovery of pan-IAP degraders via a CRBN recruiting mechanism

Seulki Park et al.

Summary: Inhibitors of apoptosis proteins (IAPs) regulate cell survival and cell death. In this study, a new PROTAC strategy was developed to degrade cIAP1/2 and XIAP, thereby inhibiting immune response and cancer cell migration and invasion.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2023)

Article Biochemistry & Molecular Biology

Design and characterization of a heterobifunctional degrader of KEAP1

Hao Chen et al.

Summary: A proteolysis targeting chimera (PROTAC) that depletes KEAP1 and activates the NRF2 antioxidant response has been developed as a potential strategy to treat diseases caused by oxidative stress. The optimized PROTAC 14 demonstrated potent KEAP1 degradation and increased expression of antioxidant proteins, effectively preventing cell death induced by reactive oxygen species. This approach presents an alternative therapeutic strategy for oxidative stress-related diseases.

REDOX BIOLOGY (2023)

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)

Article Biochemistry & Molecular Biology

Targeted protein degradation and drug discovery

Mikihiko Naito

Summary: Targeted protein degradation is a novel approach for drug discovery and basic research, involving the induction of ubiquitination and proteasomal degradation of target proteins. Various types of degrader molecules have been developed, allowing the rational development of novel degraders for specific proteins of interest.

JOURNAL OF BIOCHEMISTRY (2022)

Article Chemistry, Medicinal

Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation

Jianyu Yan et al.

Summary: PROTACs is a rapidly growing technology with many advantages over directly inhibiting protein activity. In addition to traditional PROTACs, emerging types of PROTACs are rising, with advantages including high selectivity, low toxicity, and improved therapeutic effects.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Article Biochemistry & Molecular Biology

Exploring the target scope of KEAP1 E3 ligase-based PROTACs

Guangyan Du et al.

Summary: Targeted protein degradation (TPD) employs small molecules to recruit E3 ubiquitin ligases near the proteins of interest, leading to their degradation. In this study, we generated KEAP1-recruiting degraders using a KEAP1 inhibitor and successfully targeted BET family and FAK proteins. However, we found that KEAP1 had a narrow target scope as compared to CRBN-recruiting degraders. By linking the KEAP1-binding ligand to a CRBN-binding ligand, we developed a molecule that induced KEAP1 degradation but not CRBN degradation.

CELL CHEMICAL BIOLOGY (2022)

Review Chemistry, Multidisciplinary

PROTACs: past, present and future

Ke Li et al.

Summary: PROTACs are a type of molecules with novel event-driven mechanism, offering multiple advantages over traditional inhibitors, such as catalytic nature and targeted protein degradation, which may lead to improved therapeutic outcomes with reduced toxicity. However, further research and development efforts are needed to fully explore their potential.

CHEMICAL SOCIETY REVIEWS (2022)

Article Pharmacology & Pharmacy

Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

Shipeng He et al.

Summary: The novel homo-PROTAC strategy induces self-degradation of MDM2, showing efficient disruption of MDM2-P53 interaction in non-small cell lung cancer cells. In in vivo studies, the homo-PROTAC exhibits potent antitumor activity targeting A549 xenografts, demonstrating its potential as a safe therapy for cancer treatment.

ACTA PHARMACEUTICA SINICA B (2021)

News Item Biotechnology & Applied Microbiology

Targeted protein degraders crowd into the clinic

Asher Mullard

NATURE REVIEWS DRUG DISCOVERY (2021)

Review Chemistry, Multidisciplinary

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Carlotta Cecchini et al.

Summary: PROTACs are heterobifunctional degraders that eliminate targeted proteins by utilizing the UPS system, showing potential as an appealing technology in drug discovery. However, their poor cellular permeability due to high molecular weight and large polar surface area poses challenges, requiring strategies and biological tools to enhance cellular uptake.

FRONTIERS IN CHEMISTRY (2021)

Article Biochemistry & Molecular Biology

Von Hippel-Lindau (VHL) small-molecule inhibitor binding increases stability and intracellular levels of VHL protein

Julianty Frost et al.

Summary: VHL inhibitors selectively activate HIF response and have potential therapeutic effects by stabilizing VHL isoforms. These compounds exhibit different antagonistic effects upon acute versus prolonged treatment in cells.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

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)

Article Biochemistry & Molecular Biology

Selective degradation-inducing probes for studying cereblon (CRBN) biology

Chelsea E. Powell et al.

Summary: Targeted protein degradation has emerged as a rapidly growing area in drug discovery and development, offering a method for selective protein knockdown through chemical probes that is orthogonal to genetic knockdowns. Researchers developed highly selective CRBN degraders and demonstrated their utility as chemical knockdown reagents for studying CRBN-dependent processes.

RSC MEDICINAL CHEMISTRY (2021)

Article Biochemical Research Methods

DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput

Vadim Demichev et al.

NATURE METHODS (2020)

Review Biochemistry & Molecular Biology

Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

George M. Burslem et al.

Article Chemistry, Medicinal

Medicinal Chemistry of Inhibiting RING-Type E3 Ubiquitin Ligases

Nicole Blaquiere et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

Review Cell Biology

Future Therapeutic Directions for Smac-Mimetics

Emma Morrish et al.

CELLS (2020)

Review Chemistry, Multidisciplinary

Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective

Laura M. Luh et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2020)

Article Biochemical Research Methods

diaPASEF: parallel accumulation-serial fragmentation combined with data-independent acquisition

Florian Meier et al.

NATURE METHODS (2020)

Review Biochemistry & Molecular Biology

PROTACs: An Emerging Therapeutic Modality in Precision Medicine

Dhanusha A. Nalawansha et al.

CELL CHEMICAL BIOLOGY (2020)

Article Chemistry, Multidisciplinary

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Christian Steinebach et al.

CHEMICAL SCIENCE (2020)

Article Biochemistry & Molecular Biology

Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Miriam Girardini et al.

BIOORGANIC & MEDICINAL CHEMISTRY (2019)

Article Biochemistry & Molecular Biology

Rapid and Reversible Knockdown of Endogenously Tagged Endosomal Proteins via an Optimized HaloPROTAC Degrader

Hannah Tovell et al.

ACS CHEMICAL BIOLOGY (2019)

Article Chemistry, Medicinal

Development of selective small molecule MDM2 degraders based on nutlin

Bo Wang et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2019)

Article Biochemistry & Molecular Biology

Development of targeted protein degradation therapeutics

Philip P. Chamberlain et al.

NATURE CHEMICAL BIOLOGY (2019)

Article Multidisciplinary Sciences

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase

Blake E. Smith et al.

NATURE COMMUNICATIONS (2019)

Article Chemistry, Multidisciplinary

PROTAC-mediated crosstalk between E3 ligases

Christian Steinebach et al.

CHEMICAL COMMUNICATIONS (2019)

Article Biochemistry & Molecular Biology

Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor degradation

Nobumichi Ohoka et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2018)

Review Pharmacology & Pharmacy

Small Molecule Modulators of RING-Type E3 Ligases: MDM and Cullin Families as Targets

Emil Bulatov et al.

FRONTIERS IN PHARMACOLOGY (2018)

Article Biochemistry & Molecular Biology

Homo-PROTACs for the Chemical Knockdown of Cereblon

Christian Steinebach et al.

ACS CHEMICAL BIOLOGY (2018)

Editorial Material Chemistry, Medicinal

Drugging the undruggabl: targeting challenging E3 ligases for personalized medicine

Carles Galdeano

FUTURE MEDICINAL CHEMISTRY (2017)

Article Multidisciplinary Sciences

Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

Chiara Maniaci et al.

NATURE COMMUNICATIONS (2017)

Review Chemistry, Multidisciplinary

Small-Molecule Modulation of Protein Homeostasis

George M. Burslem et al.

CHEMICAL REVIEWS (2017)

Article Multidisciplinary Sciences

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Kanak Raina et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2016)

Article Biochemistry & Molecular Biology

Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

Michael Zengerle et al.

ACS CHEMICAL BIOLOGY (2015)

Review Biochemistry & Molecular Biology

Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation

Emil Bulatov et al.

BIOCHEMICAL JOURNAL (2015)

Article Oncology

Promises and Challenges of Smac Mimetics as Cancer Therapeutics

Simone Fulda

CLINICAL CANCER RESEARCH (2015)

Review Biotechnology & Applied Microbiology

IAP proteins as targets for drug development in oncology

Laurence Dubrez et al.

ONCOTARGETS AND THERAPY (2013)

Review Biotechnology & Applied Microbiology

Targeting IAP proteins for therapeutic intervention in cancer

Simone Fulda et al.

NATURE REVIEWS DRUG DISCOVERY (2012)

Article Biochemistry & Molecular Biology

Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization

Rebecca Feltham et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2011)

Article Multidisciplinary Sciences

Antagonists Induce a Conformational Change in cIAP1 That Promotes Autoubiquitination

Erin C. Dueber et al.

SCIENCE (2011)

Article Biochemistry & Molecular Biology

IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis

Eugene Varfolomeev et al.

Article Biochemistry & Molecular Biology

IAP antagonists target cIAP1 to induce TNFα- dependent apoptosis

James E. Vince et al.

Article Chemistry, Medicinal

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer

TK Oost et al.

JOURNAL OF MEDICINAL CHEMISTRY (2004)

Article Biochemical Research Methods

Pharmaceutical profiling method for lipophilicity and integrity using liquid chromatography-mass spectrometry

EH Kerns et al.

JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES (2003)

Review Cell Biology

IAP proteins: Blocking the road to death's door

GS Salvesen et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2002)

Article Multidisciplinary Sciences

Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain

ZH Liu et al.

NATURE (2000)

Article Multidisciplinary Sciences

Structural basis of IAP recognition by Smac/DIABLO

G Wu et al.

NATURE (2000)

Article Multidisciplinary Sciences

Structural and biochemical basis of apoptotic activation by Smac/DIABLO

JJ Chai et al.

NATURE (2000)