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Multipathway regulation induced by 4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer

Fan-Wei Yang1, Te-Lun Mai2, Ying-Chung Jimmy Lin2,3,4

  • 1Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Archiv Der Pharmazie
|February 5, 2024
PubMed

Insights

Researchers developed a novel compound, GL24, using phenotypic drug discovery for triple-negative breast cancer (TNBC). GL24 inhibits TNBC cell growth by activating endoplasmic reticulum stress-dependent tumor suppressive signals, leading to cell-cycle arrest and apoptosis.

Area of Science:

  • Drug discovery and development
  • Cancer biology
  • Molecular pharmacology

Background:

  • Phenotypic drug discovery (PDD) is crucial for complex diseases like triple-negative breast cancer (TNBC), which has high heterogeneity and limited therapeutic targets.
  • TNBC presents significant challenges due to its invasive nature, metastatic potential, and lack of targeted therapies.
  • Novel therapeutic strategies are urgently needed for effective TNBC treatment.

Purpose of the Study:

  • To synthesize and evaluate novel small molecules based on a 4-(phenylsulfonyl)morpholine pharmacophore for TNBC treatment.
  • To identify the molecular mechanisms underlying the tumor-suppressive effects of promising drug candidates.
  • To explore the potential of endoplasmic reticulum (ER) stress pathways in TNBC therapy.

Main Methods:

  • Synthesis of 23 novel 4-(phenylsulfonyl)morpholine derivatives.
  • In vitro evaluation of anti-cancer activity using MDA-MB-231 TNBC cell line.
  • Transcriptomic analysis, including gene ontology (GO), gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.

Main Results:

  • GL24, a novel derivative, demonstrated potent inhibition of TNBC cell growth with a low IC50 value (0.90 µM).
  • Transcriptomic analyses revealed that GL24 treatment activates ER stress-dependent tumor suppressive signals.
  • Key pathways identified include unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets, all contributing to cell-cycle arrest and apoptosis.

Conclusions:

  • The novel compound GL24 shows significant potential as an anti-TNBC agent.
  • GL24 exerts its tumor-suppressive effects through the induction of ER stress-dependent pathways.
  • Further investigation into GL24 could lead to new therapeutic strategies for triple-negative breast cancer.
Keywords:
4‐(phenylsulfonyl)morpholine derivativesphenotypic drug discoverytranscriptomic analysestriple negative breast cancer

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