Novel quinazolin-4(3H)-one based Cyclin K degraders regulate alternative polyadenylation activity

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Biology

Background:

• Phenotypic screening is a key method for discovering compounds with novel mechanisms of action.
• Molecular glues, identified via phenotypic screening, induce target protein degradation by forming E3 ligase ternary complexes.
• Alternative polyadenylation (APA) is a crucial post-transcriptional regulatory process.

Purpose of the Study:

• To identify novel compounds regulating cellular phenotypes through phenotypic screening.
• To elucidate the mechanism of action of a novel Cyclin K degrader identified through phenotypic screening.
• To develop improved chemical tools for studying Cyclin K degradation and APA regulation.

Main Methods:

• Global proteomic analysis to identify protein degraders.
• Phenotypic screening for compounds regulating alternative polyadenylation.
• Mechanistic studies to determine compound-target interactions.
• Structure-activity relationship (SAR) studies to optimize compound potency.

Main Results:

• A novel molecular glue, T4, was identified as a Cyclin K degrader through phenotypic screening.
• T4 was shown to induce Cyclin K degradation, leading to the regulation of alternative polyadenylation.
• A more potent Cyclin K degrader, TR-213, was synthesized based on SAR studies of T4.
• T4 and TR-213 are structurally distinct from existing Cyclin K degraders.

Conclusions:

• T4 represents a novel chemical tool for investigating Cyclin K function and its role in APA.
• TR-213 offers enhanced potency for studying Cyclin K degradation pathways.
• These compounds provide new avenues for exploring the therapeutic potential of targeting protein degradation.