Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery

The Rise of Molecular Glues

(2021) Stuart L. Schreiber   CELL

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia

(2021) Joshua D. Hansen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

(2021) Troy A. Bemis et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma

(2020) Joshua D. Hansen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Unifying principles of bifunctional, proximity-inducing small molecules

(2020) Christopher J. Gerry et al.   Nature Chemical Biology

Crystal structure of the SALL4–pomalidomide–cereblon–DDB1 complex

(2020) Mary E. Matyskiela et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Targeting Estrogen Receptor α for degradation with PROTACs: A Promising Approach to Overcome Endocrine Resistance

(2020) Xin Lin et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

(2020) Mikołaj Słabicki et al.   NATURE

Manumycin polyketides act as molecular glues between UBR7 and P53

(2020) Yosuke Isobe et al.   Nature Chemical Biology

Rational discovery of molecular glue degraders via scalable chemical profiling

(2020) Cristina Mayor-Ruiz et al.   Nature Chemical Biology

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

(2020) Lu Lv et al.   eLife

CC-90009, a novel cereblon E3 ligase modulator targets acute myeloid leukemia blasts and leukemia stem cells

(2020) Christine Surka et al.   BLOOD

Small-molecule-induced polymerization triggers degradation of BCL6

(2020) Mikołaj Słabicki et al.   NATURE

The PROTAC technology in drug development

(2019) Yutian Zou et al.   CELL BIOCHEMISTRY AND FUNCTION

Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction

(2019) Kyle R. Simonetta et al.   Nature Communications

Next-generation characterization of the Cancer Cell Line Encyclopedia

(2019) Mahmoud Ghandi et al.   NATURE

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

Targeted protein degradation: elements of PROTAC design

(2019) Stacey-Lynn Paiva et al.   CURRENT OPINION IN CHEMICAL BIOLOGY

Development of targeted protein degradation therapeutics

(2019) Philip P. Chamberlain et al.   Nature Chemical Biology

Bifunctional chemical probes inducing protein–protein interactions

(2019) Chiara Maniaci et al.   CURRENT OPINION IN CHEMICAL BIOLOGY

Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds

(2019) Zhaoyang Li et al.   NATURE

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

(2019) Tyler B. Faust et al.   Nature Chemical Biology

Targeted protein degradation: expanding the toolbox

(2019) Matthieu Schapira et al.   NATURE REVIEWS DRUG DISCOVERY

Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

(2019) Xinlin Du et al.   STRUCTURE

Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15

(2019) Tabitha C. Ting et al.   Cell Reports

Molecular glue concept solidifies

(2019) Kheewoong Baek et al.   Nature Chemical Biology

Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex

(2019) Dirksen E. Bussiere et al.   Nature Chemical Biology

Inducing protein-protein interactions with molecular glues

(2018) Ye Che et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Plasticity in binding confers selectivity in ligand-induced protein degradation

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

Chemically induced proximity in biology and medicine

(2018) Benjamin Z. Stanton et al.   SCIENCE

SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate

(2018) Mary E. Matyskiela et al.   Nature Chemical Biology

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

(2018) Katherine A Donovan et al.   eLife

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

(2018) Quinlan L. Sievers et al.   SCIENCE

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

Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure–Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1

(2017) Joshua D. Hansen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

(2017) Taisuke Uehara et al.   Nature Chemical Biology

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

(2017) Ting Han et al.   SCIENCE

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

(2017) Nina Kerres et al.   Cell Reports

Small-Molecule PROTACS: New Approaches to Protein Degradation

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

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

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines

(2016) Channing Yu et al.   NATURE BIOTECHNOLOGY

Induced protein degradation: an emerging drug discovery paradigm

(2016) Ashton C. Lai et al.   NATURE REVIEWS DRUG DISCOVERY

CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

(2015) P. R. Hagner et al.   BLOOD

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

(2015) Jan Krönke et al.   NATURE

Phthalimide conjugation as a strategy for in vivo target protein degradation

(2015) G. E. Winter et al.   SCIENCE

Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

(2014) Eric S. Fischer et al.   NATURE

Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs

(2014) Philip P Chamberlain et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

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

Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy

(2013) J Shortt et al.   ONCOGENE

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

Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment

(2012) Yoichi Ozawa et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide

(2012) A Lopez-Girona et al.   LEUKEMIA

Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma

(2012) Yuan Xiao Zhu et al.   LEUKEMIA & LYMPHOMA

Jasmonate perception by inositol-phosphate-potentiated COI1–JAZ co-receptor

(2010) Laura B. Sheard et al.   NATURE

Autophagy fights disease through cellular self-digestion

(2008) Noboru Mizushima et al.   NATURE