Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders DOI Creative Commons
Alena Kroupova, Valentina A. Spiteri, Hirotake Furihata

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 20, 2024

Abstract The ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide recruited by most targeted protein degraders (PROTACs molecular glues) in clinical development. Biophysical structural investigation CRBN has been limited current constructs that either require co-expression with adaptor DDB1 or inadequately represent full-length protein, high-resolution structures ternary complexes remaining rare. We present design midi , a construct readily expresses from E. coli high yields as soluble, stable without DDB1. benchmark for wild-type functionality through suite biophysical techniques solve co-crystal its binary degraders. qualify an enabling tool to accelerate structure-based discovery next generation based therapeutics. One sentence summary A novel Cereblon (CRBN ) allows enablement ligand degrader

Language: Английский

Molecular glues for protein-protein interactions: Progressing toward a new dream DOI Creative Commons
Markella Konstantinidou, Michelle R. Arkin

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(6), P. 1064 - 1088

Published: May 2, 2024

SummaryThe modulation of protein-protein interactions with small molecules is one the most rapidly developing areas in drug discovery. In this review, we discuss advances over past decade (2014–2023) focusing on molecular glues (MGs)—monovalent that induce proximity, either by stabilizing native or inducing neomorphic interactions. We include both serendipitous and rational discoveries describe different approaches were used to identify them. classify compounds three main categories: degradative MGs, non-degradative MGs PPI stabilizers, self-association. Diverse, illustrative examples structural data are described detail, emphasizing elements recognition cooperative binding at interface fundamental for a MG mechanism action.Graphical abstract

Language: Английский

Citations

25
PROTACable Is an Integrative Computational Pipeline of 3-D Modeling and Deep Learning To Automate the De Novo Design of PROTACs DOI
Hazem Mslati, Francesco Gentile, Mohit Pandey

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(8), P. 3034 - 3046

Published: March 20, 2024

Proteolysis-targeting chimeras (PROTACs) that engage two biological targets at once are a promising technology in degrading clinically relevant protein targets. Since factors influence the activities of PROTACs more complex than those small molecule drug, we explored combination computational chemistry and deep learning strategies to forecast PROTAC activity enable automated design. A new method named PROTACable was developed for de novo design PROTACs, which includes robust 3-D modeling workflow model ternary complexes using library E3 ligase linker an SE(3)-equivariant graph transformer network predict newly designed PROTACs. is available https://github.com/giaguaro/PROTACable/.

Language: Английский

Citations

9
Analyzing the Linker Structure of PROTACs throughout the Induction Process: Computational Insights DOI

Yihao Li,

Xiaoxuan Zhang, Jiali Xie

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Linker structures are a crucial component of proteolysis-targeting chimeras (PROTACs) and have traditionally been designed based on empirical methods, which presents significant challenges in the development PROTACs. Current optimization strategies typically focus reducing number rotatable bonds linker to limit conformational freedom. However, this approach overlooks complexity target protein degradation process. Retrospective analyses suggest that merely adjusting is insufficient control freedom PROTACs, indicating need for new strategies. By integration computational methods such as molecular dynamics simulations, study investigates role throughout induction process, particularly its impact formation stability ternary complex. This offers potential overcoming limitations traditional strategies, reliance enhancing overall efficiency effectiveness PROTAC design.

Language: Английский

Citations

1
Proteomic approaches advancing targeted protein degradation DOI Creative Commons
Gajanan Sathe, Gopal P. Sapkota

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(11), P. 786 - 801

Published: Sept. 29, 2023

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) molecular glue (MG) degraders (MGDs) represent the most advanced approaches, with some already used in clinical settings. Despite these advances, still faces many challenges, pertaining to both development of effective, selective, tissue-penetrant understanding their mode action. In this review, we focus on progress made addressing challenges. particular, discuss utility application recent proteomic as indispensable tools enable insights into degrader development, including target engagement, selectivity, efficacy, safety,

Language: Английский

Citations

21
Mechanism of degrader-targeted protein ubiquitinability DOI Creative Commons
Charlotte Crowe, Mark A. Nakasone, Sarah Chandler

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 5, 2024

Abstract Small molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and the potential to tackle previously undrugged targets. Thermodynamically stable kinetically long-lived degrader-mediated ternary complexes can drive faster, more profound durable target degradation, however mechanistic features by which they impact on ubiquitination remain elusive. Here, we solve cryo-EM structures VHL Cullin 2 RING E3 ligase complexed degrader MZ1, protein Brd4 BD2 primed for catalysis its cognate E2-ubiquitin bound. We find that adopts favourable orientation towards E2 active site. In vitro coupled mass spectrometry illuminates patch ubiquitinable lysines one face , Lys456 showing optimal distance geometry nucleophilic attack. Our results demonstrate proficiency MZ1 in directing substrate catalysis, explains favourability ubiquitination, reveals flexibility enzyme capturing sub-optimal lysines. propose model ubiquitinability degrader-recruited targets provides blueprint further rational drug design optimization. One-Sentence Summary Structural assembly PROTAC-mediated complex whole bound structural insights specificity ubiquitination.

Language: Английский

Citations

7
Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders DOI Creative Commons
Corentin Bouvier, Rachel Lawrence,

Francesca Cavallo

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 578 - 578

Published: March 26, 2024

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding ubiquitin ligase. More generally referred as bifunctional degraders, PROTACs have led the way in field targeted protein (TPD), with several currently undergoing clinical testing. Alongside single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered viable approach for development therapeutics, driven advances rational discovery approaches. This review focuses on drug respect within proteasome system, including analysis mechanistic concepts approaches, an overview current pre-clinical degrader status oncology, neurodegenerative inflammatory disease.

Language: Английский

Citations

7
Structural Basis of Conformational Dynamics in the PROTAC‐Induced Protein Degradation DOI
Hongtao Zhao

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(14)

Published: April 24, 2024

Abstract Pronounced conformational dynamics is unveiled upon analyzing multiple crystal structures of the same proteins recruited to E3 ligases by PROTACs, and yet, largely permissive for targeted protein degradation due intrinsic mobility assemblies creating a large ubiquitylation zone. Mathematical modelling ternary on probability confirms experimental finding that complex rigidification need not correlate with enhanced degradation. Salt bridges are found prevail in PROTAC‐induced complexes, may contribute positive cooperativity prolonged half‐life. The analysis highlights importance presenting lysines close active site E2 enzyme while constraining PROTAC design achieve high efficiency.

Language: Английский

Citations

7
Targeting a lineage-specific PI3Kɣ–Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule DOI
Loïs Kelly, Justine C. Rutter, Kevin Lin

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(7), P. 1082 - 1101

Published: May 30, 2024

Language: Английский

Citations

7
Quantitative Measurement of Rate of Targeted Protein Degradation DOI
Thomas L. Lynch,

Violeta L. Marin,

Ryan A. McClure

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(7), P. 1604 - 1615

Published: July 9, 2024

Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This accomplished by using mono- or bifunctional small molecules designed induce proximity target proteins and E3 ubiquitin ligases, leading ubiquitination subsequent proteasome-dependent target. One most significant attributes TPD its proposed catalytic mechanism action, which permits substoichiometric exposure achieve desired pharmacological effects. However, apart from one in vitro study, studies supporting degraders are largely inferred based on potency. A more comprehensive understanding degrader action can help aspects compound development. To address this knowledge gap, we developed workflow for quantitative measurement rate cells. Comparing selective promiscuous BTK degrader, demonstrate both compounds function as efficient catalysts degradation, with exhibiting faster rates due ability favorable ternary complexes. By leveraging computational modeling, show highly dynamic depleted Further investigation kinase revealed better predictor optimal activity toward specific compared magnitude alone. In summary, present versatile method mapping any

Language: Английский

Citations

7
Development of PROTACs using computational approaches DOI
Jingxuan Ge,

Chang-Yu Hsieh,

Meijing Fang

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

6