The SRC family kinase inhibitor NXP900 demonstrates potent antitumor activity in squamous cell carcinomas Dash, Sweta Hanson, Sabrina King, Ben Nyswaner, Katherine Foss, Kelcie Tesi, Noelle Harvey, Mungo J.B. Navarro Marchal, Saul Abenhamar Woods, Alison Poradosu, Enrique Unciti-Broceta, Asier Carragher, Neil O. Brognard, John ESCC HNSCC Src family kinases This research was supported by the National Cancer Institute, grant number ZIA BC 011691. Medical Research Council Precision Medicine Doctoral Training Programme and Nuvectis Pharma, Inc. NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the "closed" conformation, thereby inhibiting both kinase-dependent catalytic activity and kinase-independent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active "open" conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases. This results in highly potent and specific SFK pathway inhibition. Here, we demonstrate that esophageal squamous cell carcinomas and head and neck squamous cell carcinomas are exquisitely sensitive to NXP900 treatment in cell culture and in vivo, and we identify a patient population that could benefit from treatment with NXP900. 2024-09-19T09:15:53Z 2024-09-19T09:15:53Z 2024-07-31 journal article Dash S. et al. The SRC family kinase inhibitor NXP900 demonstrates potent antitumor activity in squamous cell carcinomas. J Biol Chem. 2024 Jul 31;300(9):107615. doi: 10.1016/j.jbc.2024.107615 https://hdl.handle.net/10481/94715 10.1016/j.jbc.2024.107615 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier