Discovery of SOCS7 as a versatile E3 ligase for protein-based degraders DOI Creative Commons

Anaïs Cornebois,

Marie Sorbara,

Margot Cristol

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(5), P. 109802 - 109802

Published: April 23, 2024

Targeted protein degradation (TPD) strategy harnesses the ubiquitin-proteasome system (UPS) to degrade a of interest (POI) by bringing it into proximity with an E3 ubiquitin ligase. However, limited availability functional ligases and emergence resistance through mutations in UPS components restrict this approach. Therefore, identifying alternative suitable for TPD is important develop new degraders overcome potential mechanisms. Here, we use protein-based degrader method, fusing anti-tag intracellular antibody ligase, screen enabling tagged POI. We identify SOCS7 ligase as effective biodegrader, able deplete its target various cell lines regardless POI's subcellular localization. show utility generating SOCS7-based KRAS that inhibits mutant pancreatic cancer cells' proliferation. These findings highlight versatility valuable potent degraders.

Language: Английский

Proteome-scale discovery of protein degradation and stabilization effectors DOI
Juline Poirson, Hanna Cho,

Akashdeep Dhillon

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8009), P. 878 - 886

Published: March 20, 2024

Language: Английский

Citations

25
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
Exploring the chemical space of orally bioavailable PROTACs DOI Creative Commons
Giulia Apprato, Vasanthanathan Poongavanam, Diego García Jiménez

et al.

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(4), P. 103917 - 103917

Published: Feb. 14, 2024

A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it therefore essential to identify chemical space where orally bioavailable PROTACs are more likely be situated. this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on potential and limitations design tools. Subsequently, describe cutting-edge experimental, computational hybrid strategies based 3D which show promise for enhancing probability discovering with high

Language: Английский

Citations

18
Expanding the horizons of targeted protein degradation: A non-small molecule perspective DOI Creative Commons
Xiaowei Huang, Fengbo Wu,

Jing Ye

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Language: Английский

Citations

16
Structural and Physicochemical Features of Oral PROTACs DOI
Markus Schade, James S. Scott, Thomas G. Hayhow

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 13106 - 13116

Published: July 30, 2024

Achieving oral bioavailability with Proteolysis Targeting Chimeras (PROTACs) is a key challenge. Here, we report the in vivo pharmacokinetic properties mouse, rat, and dog of four clinical PROTACs compare an internally derived data set. We use NMR to determine 3D molecular conformations structural preorganization free solution, introduce new experimental descriptors, solvent-exposed H-bond donors (eHBD), acceptors (eHBA). derive upper limit eHBD ≤ 2 for apolar environments show greater tolerance other (eHBA, polarity, lipophilicity, weight) than Rule-of-5 compliant drugs. Within set structurally related PROTACs, that examples > have much lower those 2. summarize our findings as "Rule-of-oral-PROTACs" order assist medicinal chemists achieve this challenging space.

Language: Английский

Citations

15
Confounding Factors in Targeted Degradation of Short-Lived Proteins DOI
Vesna Vetma,

Laura Casares Perez,

J. E. Elias

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(7), P. 1484 - 1494

Published: July 3, 2024

Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural half-life is expected to affect the efficacy of degrading agents, but what extent it influences target not been systematically explored. Using simple mathematical modeling degradation, we find that natural dramatic effect on level induced by degrader agent which can pose significant hurdles screening efforts. Moreover, show upon for degraders short-lived proteins, agents stall synthesis, such GSPT1 and generally cytotoxic compounds, deceptively appear protein-degrading agents. This exemplified disappearance proteins MCL1 MDM2 treatment with doxorubicin. These findings have implications selection well type control experiments required conclude works bona fide targeted degrader.

Language: Английский

Citations

14
Benchmarking Methods for PROTAC Ternary Complex Structure Prediction DOI
Evianne Rovers, Matthieu Schapira

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(15), P. 6162 - 6173

Published: Aug. 1, 2024

Proteolysis targeting chimeras (PROTACs) are bifunctional compounds that recruit an E3 ligase to a target protein induce ubiquitination and degradation of the target. Rational optimization PROTAC requires structural model ternary complex. In absence experimental structure, computational tools have emerged attempt predict complexes. Here, we systematically benchmark three commonly used tools: PRosettaC, MOE, ICM. We find these PROTAC-focused methods produce array complex structures, including some observed experimentally, but also many significantly deviate from crystal structure. Molecular dynamics simulations show complexes may exist in multiplicity configurational states question use experimentally structures as reference for accurate predictions. The pioneering benchmarked here highlight promises challenges field be more valuable when guided by clear biophysical data. benchmarking data set provide evaluating other future modeling.

Language: Английский

Citations

12
Degraders in epigenetic therapy: PROTACs and beyond DOI Creative Commons
Xing‐Jie Dai,

Shi‐Kun Ji,

Meng‐Jie Fu

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(4), P. 1464 - 1499

Published: Jan. 1, 2024

Epigenetics refers to the reversible process through which changes in gene expression occur without changing nucleotide sequence of DNA. The is currently gaining prominence as a pivotal objective treatment cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from Food Drug Administration (FDA) for therapeutic intervention diverse diseases; many drawbacks, such limited applicability, toxicity, resistance. Since discovery first proteolysis-targeting chimeras (PROTACs) 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), TAG (dTAG), Trim-Away, specific non-genetic inhibitor apoptosis (IAP)-dependent eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight small-molecule degraders beyond PROTACs could achieve proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related methylation/demethylation related targets) via proteasomal or lysosomal pathways. present difficulties forthcoming prospects domain are also deliberated upon, may be valuable medicinal chemists when developing more potent, selective, drug-like clinical applications.

Language: Английский

Citations

11
ByeTAC: Bypassing an E3 Ligase for Targeted Protein Degradation DOI Open Access
Eslam M.H. Ali, Cody A. Loy, Darci J. Trader

et al.

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

Published: Jan. 21, 2024

Targeted protein degradation utilizing a bifunctional molecule to initiate ubiquitination and subsequent by the 26S proteasome has been shown be powerful therapeutic intervention. Many molecules, including covalent non-covalent ligands proteins of interest, have developed. The traditional target methodology targets interest in both healthy diseased cell populations, window is obtained based on overexpression targeted protein. We report here series degraders that do not rely interacting with an E3 ligase, but rather subunit, which we named ByeTACs: Bypassing Targeting Chimeras. Rpn-13 non-essential ubiquitin receptor for proteasome. Cells under significant stress or require ubiquitin-dependent survival, incorporate increase rates. reported are molecules include ligand BRD4, wish degrade. synthesized suite varying PEG chain lengths showed binder (TCL1) BRD4 (JQ1) linker 3 4 units most effective induce degradation. also demonstrate our new dependent upon activity expression levels. This establishes mechanism action ByeTACs can employed wide variety substrates.

Language: Английский

Citations

10
Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors DOI Creative Commons
Florian Wittlinger,

Blessing C. Ogboo,

Ekaterina Shevchenko

et al.

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 20, 2024

Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to dual motif architecture these variability that can be introduced differing linker structures geometries. We report a set alternatively linked EGFR simultaneously occupy ATP substrate allosteric pockets. Crystal show initial redesigned trisubstituted imidazole ATP-site inhibitor dibenzodiazepinone allosteric-site proved successful in spanning sites. The re-engineered yielded compound exhibited significantly higher potency (~60 pM) against drug-resistant L858R/T790M L858R/T790M/C797S, which was superadditive as compared parent molecules. enhanced attributed factors stemming from connection group informs strategies engineer agent design.

Language: Английский

Citations

10