2. Academic Validation
  3. Chemical modification of STL427944 toward morpholine-based 1,3,5-triazines as anticancer agents targeting FOXM1: green synthesis, biological evaluation and ADME-Tox profiling in a colorectal cancer model

Chemical modification of STL427944 toward morpholine-based 1,3,5-triazines as anticancer agents targeting FOXM1: green synthesis, biological evaluation and ADME-Tox profiling in a colorectal cancer model

  • Eur J Med Chem. 2026 Feb 15:304:118532. doi: 10.1016/j.ejmech.2025.118532.
Damian Kułaga 1,  Natalia Bosak 2,  Magda Ptaszkiewicz 2,  Julia Chrzan 2,  Katarzyna Staroń 2,  Kamila Marzec 2,  Anna K Drabczyk 2,  Izabela Siemieńska 3,  Marta Kot 4,  Gniewomir Latacz 5,  Joanna Karnafał 5,  Carlos A Velázquez-Martínez 6,  Katarzyna Malarz 7,  Anna Mrozek-Wilczkiewicz 7,  Anna Boguszewska-Czubara 8,  Katarzyna Greber 9,  Krzesimir Ciura 9
Affiliations

Affiliations

  • 1 Faculty of Chemical Engineering and Technology, Department of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155, Cracow, Poland; Institute of Veterinary Sciences, University Center of Veterinary Medicine UJ-UR, University of Agriculture in Cracow, 24/28 Mickiewicza Street, 30-059, Cracow, Poland. Electronic address: [email protected].
  • 2 Faculty of Chemical Engineering and Technology, Department of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155, Cracow, Poland.
  • 3 Institute of Veterinary Sciences, University Center of Veterinary Medicine UJ-UR, University of Agriculture in Cracow, 24/28 Mickiewicza Street, 30-059, Cracow, Poland.
  • 4 Department of Transplantation, Faculty of Medicine, Jagiellonian University Medical College, 265 Wielicka Street, 30-663, Cracow, Poland.
  • 5 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Kraków, Poland.
  • 6 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
  • 7 Chełkowski Institute of Physics, University of Silesia, 75 Pułku Piechoty 1A, 41-500, Chorzów, Poland.
  • 8 Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a Street, 20-093, Lublin, Poland.
  • 9 Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 107 General Jozef Haller Avenue, 80-416, Gdansk, Poland.
PMID: 41483507 DOI: 10.1016/j.ejmech.2025.118532
Abstract

Morpholine-based 1,3,5-triazines are a promising chemotype for Anticancer drug discovery, particularly through inhibition of transcription factor FOXM1, a key driver of colorectal Cancer (CRC) progression. In this study, we developed an ultrasound-assisted, eco-friendly synthesis of 17 new derivatives and evaluated their activity in CRC models. Compared with conventional conditions, the sonochemical protocol offered significantly shorter reaction times, more sustainable solvent use, and improved compliance with Green Chemistry Principles. Preliminary 24-h cytotoxicity screening identified compounds 14 and 15 as the most active. Compound 14 showed IC50 values of 14.9 μM (SW620), 17.5 μM (SW480), and 36.7 μM (CCD841), yielding favorable selectivity indices (2.1-2.5). It was more potent than 5-fluorouracil in SW620 cells (IC50 = 21.7 μM). Functional assays confirmed near complete inhibition of colony formation at 3 μM and suppression of cell migration at 6.25-12.5 μM. Mechanistic studies revealed downregulation of FOXM1 and its downstream effectors CCNB1 and CDC25, resulting in G2/M arrest and Apoptosis. Additional profiling showed weak PI3Kγ inhibition (IC50 = 3.5 μM), high passive permeability (Pe = 11.7 × 10-6 cm/s), and lower CYP3A4/2D6 interference compared with the reference compounds. The inhibition of colony formation and suppression of cell migration, the key features of the CSC phenotype, suggest that compound 14 effectively targets the populations responsible for self-renewal and metastasis. Its high activity in the CSC-rich SW620 line, including superior potency to 5-fluorouracil, further underscores its therapeutic potential for treating advanced resistant colorectal Cancer. In vivo validation using a zebrafish xenograft model demonstrated that compound 14 reduced tumor growth, with the strongest effect observed in the metastatic SW620 line. Overall, compound 14 significantly outperformed the original hit (STL427944), achieving FOXM1 inhibition at <12.5 μM (vs. 25-50 μM for STL). This marks it as a next-generation FOXM1-targeting lead, combining potent and selective Anticancer activity with sustainable synthesis, and positioning it as a strong candidate for further preclinical development.

Keywords

Anticancer agent; Cancer stem cells; Colorectal cancer; FOXM1; Sonochemistry; Triazines.

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