2. Academic Validation
  3. A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer

A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer

  • Cell Chem Biol. 2024 Jul 9:S2451-9456(24)00273-3. doi: 10.1016/j.chembiol.2024.06.012.
Metin Cetin 1,  Ozge Saatci 1,  Abdol-Hossein Rezaeian 2,  Chintada Nageswara Rao 2,  Chad Beneker 2,  Kukkamudi Sreenivas 2,  Harrison Taylor 3,  Breanna Pederson 4,  Ioulia Chatzistamou 5,  Brian Buckley 6,  Susan Lessner 4,  Peggi Angel 3,  Campbell McInnes 2,  Ozgur Sahin 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • 3 Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Bruker-MUSC Center of Excellence, Clinical Glycomics, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 4 Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
  • 5 Department of Pathology, Microbiology & Immunology, University of South Carolina, Columbia, SC 29208, USA.
  • 6 Small Molecule Screening Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
  • 7 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.
PMID: 39043186 DOI: 10.1016/j.chembiol.2024.06.012
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.

Keywords

ECM; FAK; LOX inhibitor; ROS; TNBC chemoresistance; collagen architecture; lysyl oxidase.

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