Systematic Targeting of Protein Complexes with Molecular COUPLrs

Area of Science:

• Chemical Biology
• Oncology
• Proteomics

Background:

• Small molecules targeting protein-protein interactions are crucial in cell biology and cancer research.
• Limited chemical starting points exist for probing complex protein interactions.
• Developing novel chemical modalities is essential for expanding therapeutic strategies.

Purpose of the Study:

• To develop a novel chemical platform for discovering and targeting protein complexes.
• To identify new protein classes and assemblies amenable to small molecule modulation.
• To engineer degraders for oncogenic fusion proteins and explore therapeutic applications.

Main Methods:

• Development of molecular COUPLrs (compounds with two cysteine-reactive warheads).
• Utilized the CONNECT chemical proteomic platform to identify targetable proteins and complexes.
• Optimized a COUPLr against the EML4-ALK oncogenic fusion protein.

Main Results:

• Identified 171 targetable protein classes, including mutant-selective and non-traditional assemblies.
• Developed a COUPLr that engages EML4-ALK, remodels its dynamics, disrupts signaling, and induces proteasomal degradation.
• Demonstrated that FDA-approved drugs can be converted into COUPLrs, conferring new degradation capabilities.

Conclusions:

• Molecular COUPLrs provide an unbiased framework for discovering and characterizing protein complexes.
• This modality expands the scope of small molecule-based protein targeting.
• COUPLrs offer a versatile strategy to engineer new functional properties into existing therapeutics, particularly for cancer treatment.