Targeted protein degradation: expanding the toolbox

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

(2019) Antonio Cuadrado et al.   NATURE REVIEWS DRUG DISCOVERY

A chemical approach for global protein knockdown from mice to non-human primates

(2019) Xiuyun Sun et al.   Cell Discovery

First targeted protein degrader hits the clinic

(2019) Asher Mullard   NATURE REVIEWS DRUG DISCOVERY

Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

(2019) Johannes Popow et al.   JOURNAL OF MEDICINAL CHEMISTRY

In Silico Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application

(2019) Michael L. Drummond et al.   Journal of Chemical Information and Modeling

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

(2019) Baishan Jiang et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding

(2019) Christopher P. Tinworth et al.   ACS Chemical Biology

Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications

(2019) Carl C. Ward et al.   ACS Chemical Biology

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

(2019) Lu Zhang et al.   MOLECULAR CANCER THERAPEUTICS

Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

(2019) M Catarina Silva et al.   eLife

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

(2019) Scott D. Edmondson et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16

(2019) Xiaoyu Zhang et al.   Nature Chemical Biology

Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase

(2019) Zhuoyao Chen et al.   STRUCTURE

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

(2018) Dario Neri et al.   Annual Review of Biochemistry

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

(2018) Alexandru D. Buhimschi et al.   BIOCHEMISTRY

The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons

(2018) Itay Koren et al.   CELL

Targeted protein degradation and the enzymology of degraders

(2018) Stewart L Fisher et al.   CURRENT OPINION IN CHEMICAL BIOLOGY

Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway

(2018) Mengchen Lu et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

(2018) Chelsea E. Powell et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

(2018) Chong Qin et al.   JOURNAL OF MEDICINAL CHEMISTRY

Plasticity in binding confers selectivity in ligand-induced protein degradation

(2018) Radosław P. Nowak et al.   Nature Chemical Biology

Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands

(2018) Lara N. Gechijian et al.   Nature Chemical Biology

Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway

(2018) Cheng Dong et al.   Nature Chemical Biology

Delineating the role of cooperativity in the design of potent PROTACs for BTK

(2018) Adelajda Zorba et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

(2018) Marios G. Koliopoulos et al.   Nature Communications

Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach

(2018) Zuni I. Bassi et al.   ACS Chemical Biology

A Cyclic Peptide Inhibitor of the iNOS–SPSB Protein–Protein Interaction as a Potential Anti-Infective Agent

(2018) Maiada M. Sadek et al.   ACS Chemical Biology

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

(2018) William McCoull et al.   ACS Chemical Biology

UbiHub: a data hub for the explorers of ubiquitination pathways

(2018) Lihua Liu et al.   BIOINFORMATICS

Bruton's Tyrosine Kinase degradation as a therapeutic strategy for cancer

(2018) Dennis Dobrovolsky et al.   BLOOD

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53

(2018) John Hines et al.   CANCER RESEARCH

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

(2018) Vittoria Zoppi et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression

(2018) Yangbing Li et al.   JOURNAL OF MEDICINAL CHEMISTRY

Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation

(2018) Philipp M. Cromm et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase

(2018) Domniţa-Valeria Rusnac et al.   MOLECULAR CELL

Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN

(2018) Quinlan L. Sievers et al.   SCIENCE

Cullin 3, a cellular scripter of the non-proteolytic ubiquitin code

(2018) Katerina Jerabkova et al.   SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY

In VivoKnockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)

(2017) Nobumichi Ohoka et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP)

(2017) Emiliano Tamanini et al.   JOURNAL OF MEDICINAL CHEMISTRY

Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1

(2017) Andrew P. Crew et al.   JOURNAL OF MEDICINAL CHEMISTRY

Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

(2017) Ian Churcher   JOURNAL OF MEDICINAL CHEMISTRY

A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos

(2017) Mary E. Matyskiela et al.   JOURNAL OF MEDICINAL CHEMISTRY

Disease Association and Druggability of WD40 Repeat Proteins

(2017) Richard Song et al.   JOURNAL OF PROTEOME RESEARCH

Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling

(2017) Markus Brockmann et al.   NATURE

An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

(2017) Wei Qi et al.   Nature Chemical Biology

Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

(2017) Calla M Olson et al.   Nature Chemical Biology

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

(2017) Taisuke Uehara et al.   Nature Chemical Biology

Structural basis of PROTAC cooperative recognition for selective protein degradation

(2017) Morgan S Gadd et al.   Nature Chemical Biology

The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex

(2017) Yupeng He et al.   Nature Chemical Biology

Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells

(2017) Robin M Meyers et al.   NATURE GENETICS

WD40 repeat domain proteins: a novel target class?

(2017) Matthieu Schapira et al.   NATURE REVIEWS DRUG DISCOVERY

Degrons in cancer

(2017) Bálint Mészáros et al.   Science Signaling

Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex

(2017) Teresa A.F. Cardote et al.   STRUCTURE

Degrons in cancer

(2017) Bálint Mészáros et al.   Science Signaling

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

(2016) Siyuan Zheng et al.   CANCER CELL

Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation

(2016) Daniel C. Scott et al.   CELL

Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor

(2016) Colleen A. McGourty et al.   CELL

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery

(2016) Thomas G. Davies et al.   JOURNAL OF MEDICINAL CHEMISTRY

A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

(2016) Mary E. Matyskiela et al.   NATURE

Molecular mechanism of APC/C activation by mitotic phosphorylation

(2016) Suyang Zhang et al.   NATURE

Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase

(2016) Georg Petzold et al.   NATURE

Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1

(2016) Frederick C. Nucifora et al.   Nature Communications

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

(2015) Dennis L. Buckley et al.   ACS Chemical Biology

Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL

(2015) Ashton C. Lai et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

WSB1 promotes tumor metastasis by inducing pVHL degradation

(2015) Jung Jin Kim et al.   GENES & DEVELOPMENT

Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP

(2015) Gianni Chessari et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor

(2015) Wylie S. Palmer et al.   JOURNAL OF MEDICINAL CHEMISTRY

Atomic structure of the APC/C and its mechanism of protein ubiquitination

(2015) Leifu Chang et al.   NATURE

Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

(2015) Jan Krönke et al.   NATURE

Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia

(2015) Florian Grebien et al.   Nature Chemical Biology

Catalytic in vivo protein knockdown by small-molecule PROTACs

(2015) Daniel P Bondeson et al.   Nature Chemical Biology

KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination

(2015) H Y Chen et al.   ONCOGENE

Tissue-based map of the human proteome

(2015) M. Uhlen et al.   SCIENCE

Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes

(2015) A. Yatsu et al.   Biology Open

Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins

(2015) Giovanni Smaldone et al.   PLoS One

The Structural Differences between a Glycoprotein Specific F-Box Protein Fbs1 and Its Homologous Protein FBG3

(2015) Taichi Kumanomidou et al.   PLoS One

KLHL12 Promotes Non-Lysine Ubiquitination of the Dopamine Receptors D4.2 and D4.4, but Not of the ADHD-Associated D4.7 Variant

(2015) Kamila Skieterska et al.   PLoS One

Structural and biochemical characterization of the KLHL3–WNK kinase interaction important in blood pressure regulation

(2014) Frances-Rose Schumacher et al.   BIOCHEMICAL JOURNAL

Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C

(2014) Katharine L. Sackton et al.   NATURE

Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif

(2014) Yingying Guo et al.   NATURE

Targeting bromodomains: epigenetic readers of lysine acetylation

(2014) Panagis Filippakopoulos et al.   NATURE REVIEWS DRUG DISCOVERY

Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN

(2013) Anita K. Gandhi et al.   BRITISH JOURNAL OF HAEMATOLOGY

Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)

(2013) Shiqian Qi et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Structural Basis for Cul3 Protein Assembly with the BTB-Kelch Family of E3 Ubiquitin Ligases

(2013) Peter Canning et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Molecular Architecture of the Ankyrin SOCS Box Family of Cul5-Dependent E3 Ubiquitin Ligases

(2013) João R.C. Muniz et al.   JOURNAL OF MOLECULAR BIOLOGY

A Comprehensive Mathematical Model for Three-Body Binding Equilibria

(2013) Eugene F. Douglass et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket

(2013) Weiman Xing et al.   NATURE

SOCS3 binds specific receptor–JAK complexes to control cytokine signaling by direct kinase inhibition

(2013) Nadia J Kershaw et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells

(2013) J. Kronke et al.   SCIENCE

The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins

(2013) G. Lu et al.   SCIENCE

The Ubiquitin Code

(2012) David Komander et al.   Annual Review of Biochemistry

The SOCS box-Adapting proteins for ubiquitination and proteasomal degradation

(2012) Edmond M. Linossi et al.   IUBMB LIFE

Ubiquitin-dependent regulation of COPII coat size and function

(2012) Lingyan Jin et al.   NATURE

Targeting IAP proteins for therapeutic intervention in cancer

(2012) Simone Fulda et al.   NATURE REVIEWS DRUG DISCOVERY

Crystal Structure of Human ASB9-2 and Substrate-Recognition of CKB

(2012) Xiangwei Fei et al.   PROTEIN JOURNAL

The Molecular Basis of CRL4DDB2/CSA Ubiquitin Ligase Architecture, Targeting, and Activation

(2011) Eric S. Fischer et al.   CELL

Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein

(2011) Keiichiro Okuhira et al.   FEBS LETTERS

Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

(2010) Panagis Filippakopoulos et al.   JOURNAL OF MOLECULAR BIOLOGY

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

(2010) Yukihiro Itoh et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Identification of a Primary Target of Thalidomide Teratogenicity

(2010) T. Ito et al.   SCIENCE

Pentameric Assembly of Potassium Channel Tetramerization Domain-Containing Protein 5

(2009) Irina S. Dementieva et al.   JOURNAL OF MOLECULAR BIOLOGY

Nonproteolytic Functions of Ubiquitin in Cell Signaling

(2009) Zhijian J. Chen et al.   MOLECULAR CELL

Structures of SPOP-Substrate Complexes: Insights into Molecular Architectures of BTB-Cul3 Ubiquitin Ligases

(2009) Min Zhuang et al.   MOLECULAR CELL

Trim24 targets endogenous p53 for degradation

(2009) Kendra Allton et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase

(2009) Qing Zhang et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

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

(2008) Ashley R. Schneekloth et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Characterization of Cullin-box Sequences That Direct Recruitment of Cul2-Rbx1 and Cul5-Rbx2 Modules to Elongin BC-based Ubiquitin Ligases

(2008) Nawel Mahrour et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation

(2008) Keiko Sekine et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Diversity of degradation signals in the ubiquitin–proteasome system

(2008) Tommer Ravid et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY