2. Academic Validation
  3. Design, synthesis and biological evaluation of 2-phenylquinoxaline carbonyl piperazine derivatives as novel FASN inhibitors with anticancer activity

Design, synthesis and biological evaluation of 2-phenylquinoxaline carbonyl piperazine derivatives as novel FASN inhibitors with anticancer activity

  • Bioorg Chem. 2025 Jun 21:163:108697. doi: 10.1016/j.bioorg.2025.108697.
Shailendra Singh 1,  Subarno Paul 2,  Fábio G Martins 3,  Sérgio F Sousa 3,  Chanakya N Kundu 2,  Chandrabose Karthikeyan 4,  N S Hari Narayana Moorthy 5
Affiliations

Affiliations

  • 1 Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, Madhya Pradesh 484887, India; KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh 522302, India.
  • 2 School of Biotechnology, KIIT Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India.
  • 3 UCIBIO-Applied Molecular Biosciences Unit, BioSIM-Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, Porto 4200319, Portugal; Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculdade de Medicina, Universidade do Porto, Porto 4200319, Portugal.
  • 4 Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, Madhya Pradesh 484887, India. Electronic address: karthikeyanchandrabose@gmail.com.
  • 5 Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, Madhya Pradesh 484887, India. Electronic address: hari.nmoorthy@gmail.com.
PMID: 40578172 DOI: 10.1016/j.bioorg.2025.108697
Abstract

Overexpression of fatty acid synthase (FASN) has been linked to the advancement of various cancers. FASN caters to the increased demand for lipids within tumor cells, facilitating tumor growth and progression, making it an attractive target for Anticancer drug discovery. Herein we report a novel series of 2-phenylquinoxaline-6-carboxylic acid derivatives as novel potent FASN inhibitors with Anticancer potential. Structure-activity relationship analysis demonstrated that all the synthesized compounds showed potent and selective cytotoxicity against the three Cancer cell lines evaluated with IC50 values less than 10 μM. QNX-10 was identified as a promising lead molecule as it elicited potent FASN inhibition and selective cytotoxicity against the colorectal (HCT-116, Caco-2 cell lines) and breast Cancer (MCF-7 cell line). Notably, QNX-10 induces Apoptosis and cell cycle arrest at S-phase in HCT-116 cells in a dose-dependent manner. Western blot analysis indicated that QNX-10 inhibits FASN and promotes Apoptosis in HCT-116 cells by upregulating pro-apoptotic protein Bax and downregulating anti-apoptotic protein Bcl-xL. Molecular docking and MD simulation studies with QNX-10 revealed the binding mode of the compound to the KR domain of FASN. Taken together, the study establishes compound QNX-10 to be a promising lead candidate for the development of Anticancer therapeutics targeting the FASN enzyme.

Keywords

Apoptosis Inducer; Cancer; Cell Cycle Arrest; Fatty acid synthase; MD Simulation; Phenylquinoxaline.

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