2023
DOI: 10.1021/jacs.2c11098
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Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence

Abstract: Only around 20% of the human proteome is considered to be druggable with small-molecule antagonists. This leaves some of the most compelling therapeutic targets outside the reach of ligand discovery. The concept of targeted protein degradation (TPD) promises to overcome some of these limitations. In brief, TPD is dependent on small molecules that induce the proximity between a protein of interest (POI) and an E3 ubiquitin ligase, causing ubiquitination and degradation of the POI. In this perspective, we want t… Show more

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Cited by 17 publications
(13 citation statements)
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References 293 publications
(411 reference statements)
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“…This new wealth of information could motivate the retraining of AF-Multimer, which should aim to include ligand contributions, or the development of a PROTAC-focused machine-learning model aiming at the accurate prediction of ternary complex structures. While some groups have developed tools for this purpose [32][33][34][35][36] , they are typically not general because they require that the PROTAC molecule be known a priori. Within our group we developed PROTACability 25 , which by-passes this constraint and achieves satisfactory accuracy but fails to produce high quality solutions.…”
Section: Resultsmentioning
confidence: 99%
“…This new wealth of information could motivate the retraining of AF-Multimer, which should aim to include ligand contributions, or the development of a PROTAC-focused machine-learning model aiming at the accurate prediction of ternary complex structures. While some groups have developed tools for this purpose [32][33][34][35][36] , they are typically not general because they require that the PROTAC molecule be known a priori. Within our group we developed PROTACability 25 , which by-passes this constraint and achieves satisfactory accuracy but fails to produce high quality solutions.…”
Section: Resultsmentioning
confidence: 99%
“…As NGS techniques develop and multi-omics data expands, a myriad of cuttingedge tools and methods have been deployed for data integration and interpretation. For example, multi-omics profiling interfaces with AI/ML technologies enable advanced research in targeted protein degradation (TPD), pave the way toward efficient iden-tification and rational design of small-molecule degraders [40]. In addition, machine learning (ML) with two primary learning strategies (supervised and unsupervised) now has been conducted to multiomics data for a wide range of applications [41].…”
Section: Discussionmentioning
confidence: 99%
“…Unfortunately, only approximately 20% of the human proteome is druggable for an inhibitor-centric development approach. To address the critical limitations of the inhibitor-centric approach, the development of E3-associated modulators has introduced the concept of target protein degradation (TPD) as a novel pharmacologic modality 285 . Notably, proteolysis-targeting chimeras (PROTACs) have expanded the application of PPIs and provided insights into the degradation pathways for drug discovery 286 , 287 , 288 , 289 .…”
Section: Overview Of Ub and Ubl Targeted Drug Discoverymentioning
confidence: 99%