Authors
Mingyue Lv, Qingyuan Hu, Jing Liang, Man Yuan, Yang Liu, Mengzhu Zheng, Lixia Chen, Hongxi Xu, Hua Li
Published in
Bioorganic chemistry. Volume 183. Pages 110590. Sep 29, 2026. Epub Sep 29, 2026.
Abstract
Targeted protein degradation has emerged not only as a therapeutic modality but also as a useful strategy for target deconvolution. This study investigated the anti-cancer activity and pharmacological targets of the anti-psychotic drug Flupentixol using a PROTAC probe-assisted degradomics strategy. We first verified the anti-cancer activity of Flupentixol in vitro and in vivo. To facilitate target identification, we designed and synthesized a series of Flupentixol-derived PROTACs as functional chemical probes rather than therapeutic degraders, and selected F-5 as an optimized probe for degradation-based proteomic profiling. TMT-based quantitative proteomics identified SPINT2 as a candidate cellular target engaged by the Flupentixol warhead in human colon cancer LoVo cells. CETSA and DARTS assays further supported cellular engagement of SPINT2 by Flupentixol. UPS inhibition and competitive binding experiments confirmed that F-5 induced CRBN- and ubiquitin-proteasome system-dependent degradation of SPINT2. Mechanistic studies suggested that Flupentixol promoted apoptosis and inhibited migration and invasion by functionally enhancing SPINT2-mediated suppression of HGFA/ST14/HPN-dependent HGF/MET and PI3K/AKT signaling. SPINT2 knockdown experiments further supported the involvement of SPINT2 in the cellular effects of Flupentixol. This research provides molecular insight into the repurposing of Flupentixol for oncology and highlights the utility of PROTAC probe-assisted degradomics for target discovery of existing drugs.
PMID:
42826660
Bibliographic data and abstract were imported from PubMed on 03 Oct 2026.
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