2. Academic Validation
  3. Targeting the phosphoinositide 3-kinase signaling pathway and epidermal growth factor receptor: The potential of dimethylcardamonin-derived amino acids in triple-negative breast cancer therapy

Targeting the phosphoinositide 3-kinase signaling pathway and epidermal growth factor receptor: The potential of dimethylcardamonin-derived amino acids in triple-negative breast cancer therapy

  • Bioorg Chem. 2026 Mar:170:109483. doi: 10.1016/j.bioorg.2026.109483.
Pornthip Chawapun 1,  Nopawit Khamto 2,  Yazdaniyar Fajri Halimi 3,  Kraikrit Utama 4,  Sadanon Siriphong 1,  Atchara Janthong 1,  Nathupakorn Dechsupa 5,  Jiraporn Kantapan 5,  Nawee Kungwan 6,  Thanyada Rungrotmongkol 7,  Puttinan Meepowpan 8,  Padchanee Sangthong 9
Affiliations

Affiliations

  • 1 Program in Biotechnology, Multidisciplinary and Interdisciplinary School, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 2 Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.
  • 3 Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • 4 Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 5 Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 6 Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Materials Science and Technology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 7 Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
  • 8 Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 9 Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Division of Biochemistry and Biochemical innovation, Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Research Laboratory on Advanced Materials for Sensor and Biosensor Innovation, Material Science Research Center, Center of Excellent for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: [email protected].
PMID: 41539040 DOI: 10.1016/j.bioorg.2026.109483
Abstract

Targeting the phosphoinositide 3-kinase (PI3K) signaling pathway, along with the epidermal growth factor receptor (EGFR), presents a promising strategy for breast Cancer treatment. Here, dimethylcardamonin (DMC, 1), isolated from Syzygium nervosum seeds, was modified by attaching Amino acids such as serine (2h), tryptophan (2i), and tyrosine (2j) to produce new compounds. Compounds 2h-2j demonstrated most excellent inhibitory effectiveness against breast Cancer cells, with IC50 values of 4.59 ± 0.06, 5.33 ± 0.59, and 6.89 ± 0.85 μM, respectively, in MDA-MB-231 cells. These DMC derivatives not only induced DNA damage but also triggered morphological changes in breast Cancer cells. Notably, compound 2j increased sub-G0/G1 cell cycle accumulation and through the G2/M phase arrest, significantly inducing both early and late Apoptosis. It also effectively reduced mitochondrial membrane potential alterations at higher concentrations. Furthermore, the compound 2j upregulated the expression of genes like Bax, BRCA1, Caspase-3, CDKN1A, Mcl-1, and PIK3CA, potentially influencing Apoptosis via the PI3K/Akt pathway. The compound 2j significantly inhibited the MDA-MB-231 cells proliferation by downregulation of EGFR, p-EGFR, and p-AKT protein expression levels. Molecular docking studies revealed that compound 2j had a strong binding affinity and interacted closely with key catalytic residues of EGFR, outperforming erlotinib, a known EGFR Inhibitor, suggesting its potential as an anti-breast Cancer drug candidate.

Keywords

Chalcone amino acid derivative; EGFR-TK; MDA-MB-231; Molecular dynamics simulation; PI3K signaling pathway; Triple-negative breast cancer.

Figures
Products