Optimization of PROTAC Ternary Complex Using DNA Encoded Library Approach.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation via ubiquitination and proteasomal pathways.
• Optimizing PROTACs for efficient ternary complex formation with target proteins and E3 ligases is crucial but often labor-intensive.
• Current methods for PROTAC optimization can be hindered by factors like solubility and permeability.

Purpose of the Study:

• To develop an efficient method for synthesizing and screening large libraries of PROTAC molecules.
• To identify novel PROTACs with enhanced protein degradation capabilities.
• To demonstrate the utility of DNA-encoded library (DEL) technology in PROTAC discovery.

Main Methods:

• Utilized DNA-encoded library (DEL) technology for the combinatorial synthesis of a vast PROTAC library.
• Developed a parallel screening approach employing DNA barcodes to report ternary complex formation and cooperative binding.
• Implemented a dual protein affinity selection method using BRD4 as the target protein and CRBN as the E3 ligase.

Main Results:

• Successfully synthesized and screened a large PROTAC library against BRD4 and CRBN.
• Identified novel, potent BRD4 PROTACs with demonstrated structure-activity relationships (SAR).
• The DEL approach efficiently evaluated numerous PROTACs simultaneously, bypassing issues with solubility and permeability.

Conclusions:

• DNA-encoded library technology provides an efficient platform for the discovery of potent PROTACs.
• The described parallel screening method accelerates the optimization of PROTACs for targeted protein degradation.
• This approach offers a significant advancement in the development of PROTAC-based therapeutics.