Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC

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

Published: Jan. 4, 2025

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report platform named Auto-RapTAC. Based on the modular characteristic of molecule, streamlined workflow that integrates lab automation with "click chemistry" joint building-block libraries was constructed. This facilitates autonomous generation variety PROTACs, each distinct linkers E3 ligase ligands, all stored in biocompatible solutions. ready-for-screening (R4S) approach, when paired fluorescence-based assays, enables efficient assessment degradation activity high-throughput manner. further test capability platform, six PROTACs target CDK2, CDK12, BCL6 within mere 8-day time frame target. In all, this could find broad application not only but also rapid development novel heterobifunctional modalities.

Language: Английский

Rational Proteolysis Targeting Chimera Design Driven by Molecular Modeling and Machine Learning

Wiley Interdisciplinary Reviews Computational Molecular Science, Journal Year: 2025, Volume and Issue: 15(2)

Published: March 1, 2025

ABSTRACT Proteolysis targeting chimera (PROTAC) induces specific protein degradation through the ubiquitin–proteasome system and offers significant advantages over small molecule drugs. They are emerging as a promising avenue, particularly in previously “undruggable” targets. Traditional PROTACs have been discovered large‐scale experimental screening. Extensive research efforts focused on unraveling biological pharmacological functions of PROTACs, with strides made toward transitioning from empirical discovery to rational, structure‐based design strategies. This review provides an overview recent representative computer‐aided drug studies PROTACs. We highlight how utilization targeted database, molecular modeling techniques, machine learning algorithms, computational methods contributes facilitating PROTAC discovery. Furthermore, we conclude achievements field explore challenges future directions. aim offer insights references for rational

Language: Английский

Recent advances in dual PROTACs degrader strategies for disease treatment

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 279, P. 116901 - 116901

Published: Sept. 27, 2024

Language: Английский