Abstract 681: Rewiring collagen architecture using a highly potent bi-thiazole inhibitor of LOX mediates chemosensitization in triple-negative breast cancer

Abstract

Abstract Lysyl oxidase (LOX) is the founding member of the LOX family proteins and mediates the conversion of lysine residues in collagen I and elastin precursors into highly reactive aldehydes, leading to crosslinking of extracellular matrix (ECM). LOX is upregulated in aggressive tumors with high stiffness, and its higher expression correlates with metastasis, therapy resistance, and worse clinical outcome; however, relatively LOX-specific, orally bioavailable inhibitors are still lacking. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by combining a robust screening platform for drug-like molecules, cell- and recombinant protein-based assays. Structure-activity relationship analysis further identified a potent and relatively LOX-specific lead compound (LXG6403) that reduces collagen content and crosslinking, and fibronectin assembly, leading to increased chemoresponse in triple-negative breast cancer (TNBC) cell lines and PDX organoids in 3D collagen. LXG6403 shows favorable pharmacokinetic properties, reduces collagen content and crosslinking, as demonstrated by the state-of-the-art MALDI-MSI and MP-SHG analyses, respectively. This leads to better drug penetration, inhibition of FAK signaling, and induction of ROS generation/DNA damage, leading to G1 arrest and apoptosis in chemoresistant TNBC PDXs. Overall, our novel, potent, tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype. Citation Format: Metin Cetin, Ozge Saatci, Abdol-Hossein Rezaeian, Chintada N. Rao, Chad Beneker, Harrison Taylor, Breanna Pederson, Ioulia Chatzistamou, Brian Buckley, Susan Lessner, Peggi Angel, Campbell McInnes, Ozgur Sahin. Rewiring collagen architecture using a highly potent bi-thiazole inhibitor of LOX mediates chemosensitization in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 681.