Induced protein degradation: an emerging drug discovery paradigm

Small-Molecule PROTACS: New Approaches to Protein Degradation

(2016) Momar Toure et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Drugging Undruggable Molecular Cancer Targets

(2016) John S. Lazo et al.   Annual Review of Pharmacology and Toxicology

Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour

(2016) Andrew J. Wagner et al.   EUROPEAN JOURNAL OF CANCER

Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

(2016) Rory T. Coffey et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Degradation of Akt using protein-catalyzed capture agents

(2016) Ryan K. Henning et al.   JOURNAL OF PEPTIDE SCIENCE

A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

(2016) Mary E. Matyskiela et al.   NATURE

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

(2016) Georg Petzold et al.   NATURE

Drug developers delve into the cell's trash-disposal machinery

(2016) Kelly Rae Chi   NATURE REVIEWS DRUG DISCOVERY

Drug discovery in advanced prostate cancer: translating biology into therapy

(2016) Timothy A. Yap et al.   NATURE REVIEWS DRUG DISCOVERY

Biophysics in drug discovery: impact, challenges and opportunities

(2016) Jean-Paul Renaud et al.   NATURE REVIEWS DRUG DISCOVERY

Twenty years on: the impact of fragments on drug discovery

(2016) Daniel A. Erlanson et al.   NATURE REVIEWS DRUG DISCOVERY

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

(2016) Kanak Raina et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines

(2016) James Campbell et al.   Cell Reports

Analysis of nanoparticle delivery to tumours

(2016) Stefan Wilhelm et al.   Nature Reviews Materials

A Generic Platform for Cellular Screening Against Ubiquitin Ligases

(2016) Timurs Maculins et al.   Scientific Reports

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

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

Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

(2015) Michael Zengerle 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

Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging

(2015) Jeffrey L. Gustafson et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1)

(2015) S. Ramalingam et al.   ANNALS OF ONCOLOGY

RAD1901

(2015) Fiona Garner et al.   ANTI-CANCER DRUGS

Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft

(2015) Steven P. Govek et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Development of small molecules targeting the pseudokinase Her3

(2015) Sang Min Lim et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

A Kinase-Independent Role for EGF Receptor in Autophagy Initiation

(2015) Xiaojun Tan et al.   CELL

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4

(2015) Jing Lu et al.   CHEMISTRY & BIOLOGY

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia

(2015) M. Andreeff et al.   CLINICAL CANCER RESEARCH

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

(2015) A. Omlin et al.   INVESTIGATIONAL NEW DRUGS

Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts

(2015) Andiliy Lai et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

(2015) Jan Krönke et al.   NATURE

Prime time for PROTACs

(2015) Raymond J Deshaies   Nature Chemical Biology

Catalytic in vivo protein knockdown by small-molecule PROTACs

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

Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules

(2015) Shusuke Tomoshige et al.   ORGANIC & BIOMOLECULAR CHEMISTRY

Substrate degradation by the proteasome: A single-molecule kinetic analysis

(2015) Y. Lu et al.   SCIENCE

Phthalimide conjugation as a strategy for in vivo target protein degradation

(2015) G. E. Winter et al.   SCIENCE

Identification and characterization of essential genes in the human genome

(2015) T. Wang et al.   SCIENCE

Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells

(2015) Yusuke Miyazaki et al.   eLife

Small-Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System

(2014) Dennis L. Buckley et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Development and Applications of CRISPR-Cas9 for Genome Engineering

(2014) Patrick D. Hsu et al.   CELL

Chemical Biology Strategies for Posttranslational Control of Protein Function

(2014) Rishi Rakhit et al.   CHEMISTRY & BIOLOGY

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

(2014) Carles Galdeano et al.   JOURNAL OF MEDICINAL CHEMISTRY

Nature Biotechnology's academic spinouts of 2013

(2014) Aaron Bouchie et al.   NATURE BIOTECHNOLOGY

CRISPR-Cas systems for editing, regulating and targeting genomes

(2014) Jeffry D Sander et al.   NATURE BIOTECHNOLOGY

Pharmacological targeting of the pseudokinase Her3

(2014) Ting Xie et al.   Nature Chemical Biology

Targeted protein destabilization reveals an estrogen-mediated ER stress response

(2014) Kanak Raina et al.   Nature Chemical Biology

The new frontier of genome engineering with CRISPR-Cas9

(2014) J. A. Doudna et al.   SCIENCE

Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway

(2014) N Ohoka et al.   Cell Death & Disease

Measuring Residual Estrogen Receptor Availability during Fulvestrant Therapy in Patients with Metastatic Breast Cancer

(2014) Michel van Kruchten et al.   Cancer Discovery

A kinase-independent function of AKT promotes cancer cell survival

(2014) Igor Vivanco et al.   eLife

Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies

(2014) Glenn S Cowley et al.   Scientific Data

A Bidirectional System for the Dynamic Small Molecule Control of Intracellular Fusion Proteins

(2013) Taavi K. Neklesa et al.   ACS Chemical Biology

Targeting Protein-Protein Interaction by Small Molecules

(2013) Lingyan Jin et al.   Annual Review of Pharmacology and Toxicology

Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer

(2013) Robert H. Bradbury et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

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

Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression

(2013) Chia-Hsin Chan et al.   CELL

Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non-Small Cell Lung Cancer

(2013) T. Shimamura et al.   CLINICAL CANCER RESEARCH

Discontinued drugs in 2012: oncology drugs

(2013) Robert Williams   EXPERT OPINION ON INVESTIGATIONAL DRUGS

Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development

(2013) Qingjie Ding et al.   JOURNAL OF MEDICINAL CHEMISTRY

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

(2013) S. A. Loddick et al.   MOLECULAR CANCER THERAPEUTICS

Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer

(2013) Huifang Li et al.   MOLECULAR CANCER THERAPEUTICS

Antisense battles small molecule for slice of rare lipid disorder market

(2013) Gunjan Sinha   NATURE BIOTECHNOLOGY

A three-stage biophysical screening cascade for fragment-based drug discovery

(2013) Ellene H Mashalidis et al.   Nature Protocols

Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs

(2013) J. Hines et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

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

Multiplex Genome Engineering Using CRISPR/Cas Systems

(2013) L. Cong et al.   SCIENCE

Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development

(2013) Binh Vu et al.   ACS Medicinal Chemistry Letters

Small-Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α

(2012) Dennis L. Buckley et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors

(2012) M. A. Dickson et al.   ANNALS OF ONCOLOGY

Ubiquitin-Binding Proteins: Decoders of Ubiquitin-Mediated Cellular Functions

(2012) Koraljka Husnjak et al.   Annual Review of Biochemistry

Ubiquitin and Membrane Protein Turnover: From Cradle to Grave

(2012) Jason A. MacGurn et al.   Annual Review of Biochemistry

The Ubiquitin Code

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

The Androgen Receptor in Health and Disease

(2012) Takahiro Matsumoto et al.   Annual Review of Physiology

Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist

(2012) Yukihiro Itoh et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition

(2012) Mikko Taipale et al.   CELL

Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer

(2012) James S. Duncan et al.   CELL

Identification of Hydrophobic Tags for the Degradation of Stabilized Proteins

(2012) Hyun Seop Tae et al.   CHEMBIOCHEM

Inhibitor Mediated Protein Degradation

(2012) Marcus J.C. Long et al.   CHEMISTRY & BIOLOGY

Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface

(2012) Inge Van Molle et al.   CHEMISTRY & BIOLOGY

RNA-Based Therapeutics: Current Progress and Future Prospects

(2012) John C. Burnett et al.   CHEMISTRY & BIOLOGY

Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction

(2012) Dennis L. Buckley et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Greasy tags for protein removal

(2012) Taavi K. Neklesa et al.   NATURE

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

(2012) Jordi Barretina et al.   NATURE

Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy

(2012) Howard I. Scher et al.   NEW ENGLAND JOURNAL OF MEDICINE

A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity

(2012) M. Jinek et al.   SCIENCE

Development of target protein-selective degradation inducer for protein knockdown

(2011) Yukihiro Itoh et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Design, synthesis and biological evaluation of nuclear receptor-degradation inducers

(2011) Yukihiro Itoh et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer

(2011) Robert H. Bradbury et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy

(2011) Yosuke Demizu et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

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

(2011) Eric S. Fischer et al.   CELL

The secret life of kinases: functions beyond catalysis

(2011) Jens Rauch et al.   Cell Communication and Signaling

HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab

(2011) S. Modi et al.   CLINICAL CANCER RESEARCH

Special delivery: targeted therapy with small RNAs

(2011) D Peer et al.   GENE THERAPY

Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination

(2011) Jin Liu et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Biogen Idec restructures, sharpens neurology focus

(2011) Peter Mitchell   NATURE BIOTECHNOLOGY

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90

(2011) Kamalika Moulick et al.   Nature Chemical Biology

Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins

(2011) Taavi K Neklesa et al.   Nature Chemical Biology

Impact of high-throughput screening in biomedical research

(2011) Ricardo Macarron et al.   NATURE REVIEWS DRUG DISCOVERY

RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform

(2010) C. Frank Bennett et al.   Annual Review of Pharmacology and Toxicology

Targeting heat shock proteins in cancer

(2010) Gaëtan Jego et al.   CANCER LETTERS

Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF

(2010) Sonja J. Heidorn et al.   CELL

Targeting the Undruggable Proteome: The Small Molecules of My Dreams

(2010) Craig M. Crews   CHEMISTRY & BIOLOGY

Reactive oxygen species mediate hepatotoxicity induced by the Hsp90 inhibitor geldanamycin and its analogs

(2010) Yuval Samuni et al.   FREE RADICAL BIOLOGY AND MEDICINE

Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer

(2010) Angelo Di Leo et al.   JOURNAL OF CLINICAL ONCOLOGY

Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design

(2010) Andrew J. Woodhead et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

(2010) Poulikos I. Poulikakos et al.   NATURE

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

(2010) Georgia Hatzivassiliou et al.   NATURE

An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase

(2010) Stephen Orlicky et al.   NATURE BIOTECHNOLOGY

Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase

(2010) Mariam Aghajan et al.   NATURE BIOTECHNOLOGY

HSP90 at the hub of protein homeostasis: emerging mechanistic insights

(2010) Mikko Taipale et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Identification of a Primary Target of Thalidomide Teratogenicity

(2010) T. Ito et al.   SCIENCE

RING Domain E3 Ubiquitin Ligases

(2009) Raymond J. Deshaies et al.   Annual Review of Biochemistry

Quality Control Against Misfolded Proteins in the Cytosol: A Network for Cell Survival

(2009) H. Kubota   JOURNAL OF BIOCHEMISTRY

BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90

(2009) K. Lundgren et al.   MOLECULAR CANCER THERAPEUTICS

Knocking down barriers: advances in siRNA delivery

(2009) Kathryn A. Whitehead et al.   NATURE REVIEWS DRUG DISCOVERY

Building ubiquitin chains: E2 enzymes at work

(2009) Yihong Ye et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways

(2009) Brenda A. Schulman et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

The Mechanism of Ubiquitination in the Cullin-RING E3 Ligase Machinery: Conformational Control of Substrate Orientation

(2009) Jin Liu et al.   PLoS Computational Biology

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

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

Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase Activity

(2008) Zhang Weihua et al.   CANCER CELL

NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

(2008) S. A. Eccles et al.   CANCER RESEARCH

Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation

(2008) David M. Duda et al.   CELL

Targeting Hsp90: small-molecule inhibitors and their clinical development

(2008) Tony Taldone et al.   CURRENT OPINION IN PHARMACOLOGY

The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors

(2008) Tzu-Yin Lin et al.   EXPERIMENTAL HEMATOLOGY

Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation

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

Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer

(2008) A Rodriguez-Gonzalez et al.   ONCOGENE