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

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 respons

SUBMITTER: Leo IR 

PROVIDER: S-EPMC11862126 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature