Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal...

Area of Science:

• Medicinal Chemistry
• Epigenetics
• Oncology

Background:

• Pan-BET inhibitors demonstrate significant efficacy but are limited by dose-limiting toxicities in clinical trials.
• Selective targeting of specific BET bromodomains is a strategy to improve the safety profile of epigenetic agents.
• Previous research established pyridone-based inhibitors (e.g., GSK620) with notable activity.

Purpose of the Study:

• To identify and characterize novel, potent, and selective inhibitors targeting the BD2 bromodomain of the BET protein family.
• To develop drug-like compounds with an improved safety profile compared to existing pan-BET inhibitors.
• To explore novel chemical scaffolds for BET bromodomain inhibition.

Main Methods:

• Medicinal chemistry optimization starting from a pyrrole fragment.
• Structure-activity relationship (SAR) studies guided by learnings from a pyridone series.
• In vitro assays to assess potency, selectivity, and drug-like properties.

Main Results:

• Identification of potent and selective pan-BD2 inhibitors, including pyrazole 23 (GSK809) and furan 24 (GSK743).
• These novel inhibitors exhibit significantly improved solubility compared to previous pyridone-based compounds.
• The developed compounds maintain key learnings from the pyridone series, demonstrating successful knowledge transfer.

Conclusions:

• Novel pyrazole and furan derivatives represent promising drug-like inhibitors targeting the BD2 bromodomain.
• These inhibitors offer a potential therapeutic strategy with an improved safety profile for cancer treatment.
• The improved solubility profile enhances their drug-like characteristics for further development.