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ORIGINAL RESEARCH article

Front. Oncol.

Sec. Cancer Molecular Targets and Therapeutics

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1667291

Combined cellular and biochemical profiling of Bruton's tyrosine kinase inhibitor nemtabrutinib reveals potential application in MAPK-driven cancers

Provisionally accepted
Daphne  J F KluitmansDaphne J F Kluitmans1Janneke  J T M MelisJanneke J T M Melis1Esmee  Van Den BosscheEsmee Van Den Bossche1Jacob  YtsmaJacob Ytsma1Jeroen  A D M De RoosJeroen A D M De Roos1Oscar  P J Van LindenOscar P J Van Linden2Yvonne  GrobbenYvonne Grobben1Jeffrey  KooijmanJeffrey Kooijman1Guido  J R ZamanGuido J R Zaman1*
  • 1Oncolines B.V., Oss, Netherlands
  • 2Vrije Universiteit Amsterdam, Amsterdam, Netherlands

The final, formatted version of the article will be published soon.

BACKGROUND: Nemtabrutinib is a reversible inhibitor of both wild-type and acquired resistance-related mutant BTK. Since nemtabrutinib biochemically inhibits various kinases, new drug response biomarkers, cross-reactivities and differentiators may be identified. METHODS: Nemtabrutinib was profiled in a large panel of cancer cell line viability assays. The sensitivity profile of nemtabrutinib was compared with the profiles of 135 kinase inhibitors across the same cell lines. Additionally, cell line sensitivity was related to gene mutation status, gene and protein expression levels, and gene dependency scores. Potential targets were explored using biochemical assays. RESULTS: Sensitivity to nemtabrutinib is on average three times higher in BRAF-mutant versus wild-type cell lines. Consistently, the sensitivity profile of nemtabrutinib is similar to that of MEK, ERK and pan-RAF inhibitors. Furthermore, sensitivity to nemtabrutinib is correlated with high FGFR3 gene expression levels, high levels of phosphorylated MEK1 and genetic dependency on several mitogen-activated protein kinases (MAPK). Biochemical profiling confirms that nemtabrutinib inhibits several growth factor receptor tyrosine kinases and downregulates MAPK signaling via MEK. Molecular docking studies suggest that nemtabrutinib preferentially binds in the ATP-binding pocket of MEK1. CONCLUSION: Combined cancer cell panel and biochemical profiling reveals previously underappreciated cross-reactivities of nemtabrutinib indicating a potential application in MAPK-driven cancers.

Keywords: Cancer cell line proliferation, Bruton's tyrosine kinase (BTK), Bioinformactics, Kinase profiling, MAPK, Biacore

Received: 16 Jul 2025; Accepted: 07 Oct 2025.

Copyright: © 2025 Kluitmans, Melis, Van Den Bossche, Ytsma, De Roos, Van Linden, Grobben, Kooijman and Zaman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Guido J R Zaman, guido.zaman@oncolines.com

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