Design, Synthesis and Evaluation of AdSS Bisubstrate Inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Methylthioadenosine phosphorylase (MTAP) is frequently underexpressed in various cancers.
• Cancers lacking MTAP rely on adenylosuccinate synthetase (AdSS) for essential nucleic acid synthesis.
• Targeting AdSS presents a potential therapeutic strategy for MTAP-deficient tumors.

Purpose of the Study:

• To design and synthesize novel bisubstrate inhibitors targeting adenylosuccinate synthetase (AdSS).
• To evaluate the inhibitory activity of synthesized compounds against purified AdSS.
• To identify lead compounds for potential development as anti-cancer therapeutics.

Main Methods:

• Synthesis of various bisubstrate inhibitors incorporating adenosine and linker moieties.
• Biochemical evaluation of inhibitor efficacy using purified adenylosuccinate synthetase (AdSS).
• Structure-activity relationship analysis to optimize inhibitor design.

Main Results:

• Several bisubstrate inhibitors demonstrated significant inhibitory activity against AdSS.
• An adenosine derivative with a four-carbon linker to an N-formyl-N-hydroxy moiety at the 6-position showed the highest potency.
• This lead compound represents a promising scaffold for further drug development.

Conclusions:

• Adenylosuccinate synthetase (AdSS) is a viable therapeutic target in MTAP-deficient cancers.
• Novel bisubstrate inhibitors, particularly the optimized adenosine derivative, show potential for treating these cancers.
• Further preclinical development of these AdSS inhibitors is warranted.