In silico high-throughput screening system for INMT activators in prostate cancer therapy

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Prostate cancer (PCa) is a leading cause of cancer mortality in men.
• Castration-resistant prostate cancer (CRPC) presents therapeutic challenges due to drug resistance.
• Androgen receptor (AR) signaling pathway is implicated in CRPC progression and resistance.

Purpose of the Study:

• To identify novel indolethylamine-N-methyltransferase (INMT) agonists for CRPC therapy.
• To develop an AR-independent therapeutic strategy for CRPC.
• To leverage structure-based drug design for novel CRPC treatments.

Main Methods:

• Structure-based virtual screening of the ChemDiv compound library using the INMT crystal structure (PDB ID: 2A14).
• Molecular docking, MM/GBSA binding energy calculations, and molecular dynamics simulations to identify candidate compounds.
• In vitro validation using CRPC cell models (PC-3, 22RV1) to assess DMPP-4M's effects on INMT expression, proliferation, and apoptosis.

Main Results:

• Five candidate compounds were identified, with DMPP-4M showing stable binding to an allosteric site of INMT.
• DMPP-4M dose-dependently upregulated INMT, inhibited proliferation, and induced apoptosis in CRPC cells.
• DMPP-4M activated pro-apoptotic BAX, suppressed anti-apoptotic Bcl-2, and upregulated cleaved caspase-3 and PARP, while suppressing TGF-β/Smad and Wnt/β-catenin pathways.

Conclusions:

• DMPP-4M is a promising INMT-targeted therapeutic agent for CRPC.
• DMPP-4M offers a novel AR-independent therapeutic strategy for CRPC.
• Further structural optimization and in vivo studies are warranted for clinical translation.