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Identification of Novel Target DCTPP1 for Colorectal Cancer Therapy with the Natural Small-Molecule Inhibitors
Li Feng1, Xinjia Wang1, Xinrui Guo1
1State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 211198, Nanjing, People's Republic of China.
Abstract:
Colorectal cancer (CRC) is one of the most common malignant tumors. Identification of new effective drug targets for CRC and exploration of bioactive small-molecules are clinically urgent. The human dCTP pyrophosphatase 1 (DCTPP1) is a newly identified pyrophosphatase regulating the cellular nucleotide pool but remains unexplored as potential target for CRC treatment. Here, twelve unprecedented chemical architectures terpene-nonadride heterodimers (1-12) and their monomers (13-20) were isolated from endophyte Bipolaris victoriae S27. Compounds 1-12 represented the first example of terpene-nonadride heterodimers, in which nonadride monomers of 1 and 2 were also first example of 5/6 bicyclic nonadrides. A series of assays showed that 2 could repress proliferation and induce cell cycle arrest, apoptotic and autophagic CRC cell death in vitro and in vivo. Clinical cancer samples data revealed that DCTPP1 was a novel target associated with poor survival in CRC. DCTPP1 was also identified as a new target protein of 2. Mechanically, compound 2 bound to DCTPP1, inhibited its enzymatic activity, intervened with amino acid metabolic reprogramming, and exerted anti-CRC activity. Our study demonstrates that DCTPP1 was a novel potential biomarker and therapeutic target for CRC, and 2 was the first natural anti-CRC drug candidate targeting DCTPP1.
Insights
Researchers discovered a new natural compound, compound 2, that targets DCTPP1 to fight colorectal cancer (CRC). This finding offers a promising new therapeutic strategy for CRC treatment and highlights DCTPP1 as a potential biomarker.
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.
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