Expanding the ligand spaces for E3 ligases for the design of protein degraders DOI Creative Commons
Rahman Shah Zaib Saleem, Martin P. Schwalm, Stefan Knapp

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 105, P. 117718 - 117718

Published: April 12, 2024

Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based degraders evolved over past two decades and now established molecular tags that are already in clinical use, well chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for E3 ligases CRBN VHL. The large size human ligase family suggests PROTACs can be by targeting a diversity ligases, some which have restricted expression patterns with potential to design disease- or tissue-specific degraders. Indeed, many ligands been published recently, confirming druggability ligases. This review summarises recent data highlights challenges these molecules into efficient rivalling degrader systems.

Language: Английский

A CRISPR activation screen identifies FBXO22 supporting targeted protein degradation DOI
Ananya A. Basu, Chenlu Zhang,

Isabella A. Riha

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(12), P. 1608 - 1616

Published: July 4, 2024

Language: Английский

Citations

13
Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs DOI Creative Commons
Rishi R. Shah, Elena De Vita,

Preethi S. Sathyamurthi

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(6), P. 4641 - 4654

Published: March 13, 2024

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic machinery. PROTACs which ligand the E3 ligase in covalent manner attracted intense interest; however, with broad of interest (POI) scope proven challenging discover design. Here, we report structure-guided design and optimization Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides covalently bind Ser110 HIF1α binding site. We demonstrate their incorporation bifunctional degraders induces BRD4 or androgen receptor without further linker optimization. Our study discloses first VHL ligands can be implemented directly degrader design, expanding substrate PROTACs.

Language: Английский

Citations

12
Multi-tiered chemical proteomic maps of tryptoline acrylamide–protein interactions in cancer cells DOI
Evert Njomen, Rachel E. Hayward,

Kristen E. DeMeester

et al.

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(10), P. 1592 - 1604

Published: Aug. 13, 2024

Language: Английский

Citations

10
Increasing the Throughput and Reproducibility of Activity-Based Proteome Profiling Studies with Hyperplexing and Intelligent Data Acquisition DOI Creative Commons
Hanna G. Budayeva, P. Taylur, Shuai Wang

et al.

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(8), P. 2934 - 2947

Published: Jan. 22, 2024

Intelligent data acquisition (IDA) strategies, such as a real-time database search (RTS), have improved the depth of proteome coverage for experiments that utilize isobaric labels and gas phase purification techniques (i.e., SPS-MS3). In this work, we introduce inSeqAPI, an instrument application programing interface (iAPI) program enables construction novel algorithms. First, analyze biotinylated cysteine peptides from ABPP to demonstrate method within inSeqAPI performs similarly equivalent vendor method. Then, describe PairQuant, designed hyperplexing approach utilizes protein-level isotopic labeling peptide-level TMT labeling. PairQuant allows analysis 36 conditions in single sample achieves ∼98% both peptide pair partners hyperplexed experiment well 40% improvement number quantified sites compared with non-RTS acquisition. We applied study ligandable nucleus leading identification additional druggable on protein- DNA-interaction domains transcription regulators nuclear ubiquitin ligases.

Language: Английский

Citations

9
Expanding the ligand spaces for E3 ligases for the design of protein degraders DOI Creative Commons
Rahman Shah Zaib Saleem, Martin P. Schwalm, Stefan Knapp

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 105, P. 117718 - 117718

Published: April 12, 2024

Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based degraders evolved over past two decades and now established molecular tags that are already in clinical use, well chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for E3 ligases CRBN VHL. The large size human ligase family suggests PROTACs can be by targeting a diversity ligases, some which have restricted expression patterns with potential to design disease- or tissue-specific degraders. Indeed, many ligands been published recently, confirming druggability ligases. This review summarises recent data highlights challenges these molecules into efficient rivalling degrader systems.

Language: Английский

Citations

9