Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• USP25 and USP28 are deubiquitylases (DUBs) implicated in cancer and cardiac dysfunction.
• Existing dual inhibitors of USP25/USP28 show activity in the low micromolar range.

Purpose of the Study:

• To develop a novel class of potent dual USP25/USP28 inhibitors.
• To merge structural features of AZ1 and vismodegib for enhanced potency and selectivity.

Main Methods:

• Structure-based drug design incorporating features of AZ1 and vismodegib.
• Synthesis of novel small-molecule compounds.
• Inhibition assays across multiple orthogonal assays.
• Selectivity profiling against other ubiquitin-specific proteases.
• Cellular assays with a validated negative control.

Main Results:

• Newly synthesized compounds exhibit high potency for dual USP25/USP28 inhibition.
• Compounds demonstrate excellent selectivity over other DUBs.
• Validated cellular activity using a suitable negative control.

Conclusions:

• The developed compounds represent a new class of potent and selective dual USP25/USP28 inhibitors.
• These compounds serve as advanced chemical probes for studying USP25/USP28 function.
• The findings support further therapeutic development for diseases involving USP25/USP28 dysregulation.