LXG6403 is a potent, competitive and irreversible lysosomal oxidase (LOX) inhibitor that effectively inhibits cytosolic LOX activity in MDA-MB-231 cells, with an IC50 value of 1.3 uM. LXG6403 is 3.5 times more specific for LOX than LOXL2, while it has no inhibitory effect on LOXL1. LXG6403 has good pharmacokinetic properties and can change the structure of ECM/collagen and reduce the hardness of tumour.
Biological Activity
LXG6403 is a highly potent, irreversible lysyl oxidase (LOX) inhibitor, inhibits cellular LOX activity efficiently in MDA-MB-231 cells with IC50 of 1.3 uM, >3-fold selective over LOXL2 and no activity against LOXL1.
LXG6403 inhibits cellular LOX activity with IC50 values of 1.3 μM, 1.43 μM, 4.14 μM, and 3.0 μM in MDA-MB-231, HCC143, Hs-578-T, and HCC1937 cells. LXG6403 enhances chemoresponse in 3D cultures of TNBC cell lines and PDX organoids. LXG6403 diminishes collagen crosslinking/deposition and increases drug penetration in 3D culture, inhibiting FAK signaling and potentiating ROS/DNA damage axis. LXG6403 rewires collagen architecture/signaling, overcomes doxorubicin resistance in chemoresistant TNBC PDXs in vivo.
Pharmacokinetics
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[1].
References
[1] Cetin, M., Saatci, O., Rezaeian, A.-H., Rao, C. N., Beneker, C., Sreenivas, K., Taylor, H., Pederson, B., Chatzistamou, I., Buckley, B., Lessner, S., Angel, P., McInnes, C., Sahin, O. (2024). A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer. Cell Chemical Biology, 31 11, Pages 1926-1941.e11. https://doi.org/10.1016/j.chembiol.2024.06.012
