Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Intrinsically disordered proteins (IDPs) are implicated in various diseases, including cancer, making them promising drug targets.
• Targeting IDPs is challenging due to their dynamic structures, limiting conventional drug design approaches.
• Nuclear protein 1 (NUPR1), an IDP, plays a significant role in pancreatic cancer progression.

Purpose of the Study:

• To optimize the antipsychotic agent Trifluoperazine (TFP) for enhanced efficacy and reduced side effects in targeting IDPs.
• To develop novel TFP-derived compounds for pancreatic cancer therapy.
• To explore ligand-based drug design strategies for intrinsically disordered protein targets.

Main Methods:

• A multidisciplinary approach combining computer modeling, chemical synthesis, and biophysical, biochemical, and biological evaluations.
• Synthesis and screening of a TFP-derived compound library.
• In vitro and in vivo assessments of compound activity, including tumor regression and toxicity studies.

Main Results:

• A novel TFP-derived compound, ZZW-115, was identified as highly active.
• ZZW-115 demonstrated dose-dependent tumor regression in preclinical models.
• ZZW-115 induced cancer cell death via necroptosis with no observed neurological side effects.

Conclusions:

• ZZW-115 represents a promising therapeutic candidate for pancreatic cancer targeting NUPR1.
• This study validates the feasibility of ligand-based drug design for intrinsically disordered protein targets.
• The findings open new avenues for developing drugs against challenging IDP targets in oncology.