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

Highlights•A cell-based HTS identifies bi-thiazole derivatives as potent LOX inhibitors•LXG6403 is a well-tolerated potent LOX inhibitor with favorable drug-like features•LXG6403 rewires collagen architecture/signaling to overcome chemoresistance in TNBC•LXG6403 is a promising lead candidate for highly stiff drug resistant tumorsSummaryLysyl 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.