Developing degraders: principles and perspectives on design and chemical space

Area of Science:

• Drug Discovery and Medicinal Chemistry
• Chemical Biology
• Molecular Pharmacology

Background:

• Degraders (e.g., Proteolysis-Targeting Chimeras [PROTACs], SNIPERs, degronimers) represent a promising new therapeutic modality.
• Their chemical space often falls outside established guidelines like Lipinski's 'Rule of 5', presenting challenges in cell permeability and oral bioavailability.
• Understanding this unique chemical space is crucial for advancing degrader-based therapeutics and research tools.

Purpose of the Study:

• To compile and analyze a comprehensive database of chemical structures for various degrader molecules reported in peer-reviewed literature.
• To assess the chemical space occupied by optimized and first-generation degraders.
• To identify common trends and insights relevant to the 'hit-to-lead' optimization process in degrader drug discovery.

Main Methods:

• Literature mining to collect a diverse dataset of degrader chemical structures.
• Informatics-based analysis of structural properties and chemical space.
• Identification of recurring structural motifs and design strategies in successful degraders.

Main Results:

• A curated database of degrader structures, encompassing both early-stage and optimized compounds.
• Characterization of the distinct chemical space inhabited by degraders, highlighting deviations from classical drug-like properties.
• Identification of key trends and common features employed in the design and optimization of degrader molecules.

Conclusions:

• The findings offer valuable insights into the chemical space of degraders, crucial for researchers in this emerging field.
• The study provides practical pointers for designing new degraders with improved physicochemical properties.
• This work facilitates the advancement of degrader technology for both therapeutic applications and fundamental biological research.