Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining

Area of Science:

• Pharmacology
• Genomics
• Computational Biology

Background:

• Drug repurposing offers a cost-effective strategy for discovering new therapeutic indications by leveraging existing drug data.
• Polypharmacology, where a single drug interacts with multiple targets, is a key principle underlying drug repurposing.
• Large-scale biological databases are crucial for advancing polypharmacology and drug repurposing efforts.

Purpose of the Study:

• To systematically analyze polypharmacology and facilitate drug repurposing by integrating the L1000-based Connectivity Map (CMap) with the L1000FWD web tool.
• To demonstrate the utility of integrating public resources for drug discovery through proof-of-concept studies.

Main Methods:

• Integration of the next-generation L1000-based Connectivity Map (CMap) with the L1000FWD analytic web tool.
• Systematic analysis of polypharmacology and drug repurposing using integrated datasets.
• Application of the integrated platform to identify novel anti-cancer agents, specifically histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors.

Main Results:

• Identification of KM-00927 and BRD-K75081836 as novel histone deacetylase (HDAC) inhibitors.
• Discovery of mitomycin C as a topoisomerase IIB inhibitor.
• Demonstrated successful application of integrated public resources for drug repurposing.

Conclusions:

• The integration of the L1000-based CMap and L1000FWD provides a powerful platform for systematic polypharmacology analysis and drug repurposing.
• This approach highlights the value of utilizing and integrating freely available public resources for accelerating drug discovery.
• The identified compounds represent potential leads for novel anti-cancer therapies.