Identification of Novel Target DCTPP1 for Colorectal Cancer Therapy with the Natural Small-Molecule Inhibitors...

Area of Science:

• Natural Product Chemistry
• Cancer Biology
• Drug Discovery

Background:

• Colorectal cancer (CRC) is a prevalent malignancy requiring novel therapeutic targets.
• The human dCTP pyrophosphatase 1 (DCTPP1) enzyme, regulating nucleotide pools, is an unexplored target for CRC.
• Bioactive small molecules are urgently needed for effective CRC treatment.

Purpose of the Study:

• To identify novel chemical entities with anti-CRC activity.
• To explore DCTPP1 as a potential therapeutic target for colorectal cancer.
• To investigate the mechanism of action of a novel natural compound against CRC.

Main Methods:

• Isolation and structural elucidation of twelve unprecedented terpene-nonadride heterodimers and their monomers from endophyte Bipolaris victoriae S27.
• In vitro and in vivo assays to evaluate the anti-CRC effects of isolated compounds, including proliferation, cell cycle, apoptosis, and autophagy.
• Bioinformatic analysis of clinical cancer samples to correlate DCTPP1 expression with patient survival.
• Biochemical assays to identify DCTPP1 as the direct target of compound 2 and elucidate its mechanism of action.

Main Results:

• Twelve novel terpene-nonadride heterodimers (1-12) and monomers (13-20) were isolated; compounds 1 and 2 featured unique 5/6 bicyclic nonadride structures.
• Compound 2 demonstrated significant repression of CRC cell proliferation and induced cell death via apoptosis and autophagy, both in vitro and in vivo.
• DCTPP1 was identified as a novel target associated with poor CRC survival and was shown to be directly inhibited by compound 2.
• Compound 2's anti-CRC activity was mediated by binding to DCTPP1, inhibiting its enzymatic function, and disrupting amino acid metabolic reprogramming.

Conclusions:

• DCTPP1 is a novel potential biomarker and therapeutic target for colorectal cancer.
• Compound 2 represents the first natural anti-CRC drug candidate identified to target DCTPP1.
• The study provides a new avenue for CRC drug development by targeting DCTPP1 and leveraging natural products.