Targeting Helicases: Opportunities in Drug Development

DNA and RNA helicases are essential motor proteins that use ATP to unwind nucleic acid duplexes—an indispensable step in nearly every aspect of nucleic acid metabolism: replication, repair, transcription, splicing, and more. With ~95 encoded in the human genome (31 DNA, 64 RNA), they're ripe for targeting in oncology and antivirals.

Recent Momentum Spotlight:

• US FDA Fast Track for ART6043 (Polθ inhibitor) in gBRCA-mutated HER2-negative breast cancer (with Olaparib).

• Positive Phase I/II data for WRN inhibitors: RO7589831 and HRO761.

Therapeutic Momentum:

• Cancer: WRN (synthetically lethal in MSI-H tumors) leads with three inhibitors in trials—RO7589831, HRO761, NDI-219216—targeting CRC, ovarian, endometrial, gastric cancers. Positive safety/pharmacology for ART-6043 in Phase I/IIa. Others: eIF4A (DNA); DDX3, DHX9 (RNA).

Note: Novartis discontinued the development of their inhibitor HRO761, likely due to single-agent efficacy limits.

• Antivirals: Pritelivir (AIC316) and Amenamevir (ASP2151) combat HSV/VZV, bypassing nucleoside resistance. Pipeline hits alphavirus nsP2, SARS-CoV-2, HCV.

🧪 Drug Discovery Strategies:
Helicases are challenging drug targets due to complex structure and large nucleic acid interfaces. Drug development approaches include:

• ·ATPase inhibitors: Potent but often nonspecific/toxic.

• Active-site binders: Tough due to large protein-nucleic acid interfaces.

• Allosteric inhibitors: More selective, gaining traction.

Despite structural hurdles, helicases are high-value targets—with clinical programs accelerating across oncology and viral diseases.

(Images - Freepik/ChatGPT)