The SRC family kinase inhibitor NXP900 demonstrates potent anti-tumor activity in squamous cell carcinomas

Author:

Dash,Sweta

Hanson, Sabrina

King, Ben

Nyswaner, Katherine

Foss, Kelcie

Tesi,Noelle

Harvey, Mungo J B

Navarro-Marchal, Saúl A

Woods, Allison

Poradosu, Enrique

Unciti-Broceta, Asier

Carragher, Neil O

Brognard,John
Author Address

Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD 21702, USA., Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, UK, EH4 2XR; Cancer Research UK Scotland Centre, UK., Nuvectis Pharma Inc. 1 Bridge Plaza, 2nd Floor, Fort Lee, NJ, 07024, USA., Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD 21702, USA. Electronic address: john.brognard@nih.gov.,

Abstract:

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 (ESCC) and head and neck squamous cell carcinomas (HNSCC) 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. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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