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A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer.
Cetin, Metin; Saatci, Ozge; Rezaeian, Abdol-Hossein; Rao, Chintada Nageswara; Beneker, Chad; Sreenivas, Kukkamudi; Taylor, Harrison; Pederson, Breanna; Chatzistamou, Ioulia; Buckley, Brian; Lessner, Susan; Angel, Peggi; McInnes, Campbell; Sahin, Ozgur.
Afiliación
  • Cetin M; Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Saatci O; Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Rezaeian AH; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Rao CN; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Beneker C; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Sreenivas K; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Taylor H; Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Bruker-MUSC Center of Excellence, Clinical Glycomics, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Pederson B; Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
  • Chatzistamou I; Department of Pathology, Microbiology & Immunology, University of South Carolina, Columbia, SC 29208, USA.
  • Buckley B; Small Molecule Screening Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
  • Lessner S; Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
  • Angel P; Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Bruker-MUSC Center of Excellence, Clinical Glycomics, Medical University of South Carolina, Charleston, SC 29425, USA.
  • McInnes C; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • Sahin O; Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA. Electronic address: sahin@musc.edu.
Cell Chem Biol ; 2024 Jul 09.
Article en En | MEDLINE | ID: mdl-39043186
ABSTRACT
Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and in vivo. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Chem Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Chem Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos