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
  • 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: [email protected].
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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