Versatile One-Pot Synthesis of Hydrophobic Tags by Multicomponent Reactions.

Area of Science:

• Biochemistry
• Chemical Biology
• Drug Discovery

Background:

• Protein degraders are crucial in drug discovery, with HyTags being an underexplored class.
• Current HyTag synthesis is often complex, involving multiple steps and reagents.
• Developing efficient and versatile synthetic methods for HyTags is essential.

Purpose of the Study:

• To design a streamlined and sustainable multicomponent platform for HyTag synthesis.
• To generate a diverse library of HyTags with varied linkers and hydrophobic moieties.
• To investigate the degradation mechanism of novel BRD4-targeting HyTags.

Main Methods:

• Development of a versatile multicomponent reaction platform for HyTag synthesis.
• Synthesis of a series of BRD4-targeting HyTags using (+)-JQ1 as the protein of interest (POI) ligand.
• Investigation of the degradation pathway induced by compound 23, including autophagy-lysosome and ER stress markers.

Main Results:

• The multicomponent platform efficiently produced diverse HyTags in high yields.
• Compound 23, a novel BRD4-targeting HyTag, was synthesized.
• Compound 23 was found to induce BRD4 degradation through the autophagy-lysosome pathway, involving ER stress.

Conclusions:

• The developed multicomponent platform offers a sustainable and efficient approach to HyTag synthesis.
• The discovery of compound 23's degradation mechanism highlights the potential of HyTags in targeted protein degradation.
• This synthetic methodology is valuable for discovering novel and effective protein degraders.