Functional proteoform group deconvolution reveals a broader spectrum of ibrutinib off-targets

Isabelle Rose Leo, Elena Kunold, Anastasia Audrey, Marianna Tampere, Jürgen Eirich, Janne Lehtiö and Rozbeh Jafari (rozbeh.jafari@ki.se)
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Isabelle Rose Leo: Science for Life Laboratory
Elena Kunold: Science for Life Laboratory
Anastasia Audrey: University Medical Center Groningen
Marianna Tampere: Science for Life Laboratory
Jürgen Eirich: University of Münster
Janne Lehtiö: Science for Life Laboratory
Rozbeh Jafari: Science for Life Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Proteome-wide profiling has revealed that targeted drugs can have complex protein interaction landscapes. However, it’s a challenge to profile drug targets while systematically accounting for the dynamic protein variations that produce populations of multiple proteoforms. We address this problem by combining thermal proteome profiling (TPP) with functional proteoform group detection to refine the target landscape of ibrutinib. In addition to known targets, we implicate additional specific functional proteoform groups linking ibrutinib to mechanisms in immunomodulation and cellular processes like Golgi trafficking, endosomal trafficking, and glycosylation. Further, we identify variability in functional proteoform group profiles in a CLL cohort, linked to treatment status and ex vivo response and resistance. This offers deeper insights into the impacts of functional proteoform groups in a clinical treatment setting and suggests complex biological effects linked to off-target engagement. These results provide a framework for interpreting clinically observed off-target processes and adverse events, highlighting the importance of functional proteoform group-level deconvolution in understanding drug interactions and their functional impacts with potential applications in precision medicine.

Date: 2025
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DOI: 10.1038/s41467-024-54654-8

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