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Multi-Omics Analysis Reveals RNA Polymerase II Degradation as a Novel Mechanism of PF-3758309's Anti-Tumor Activity

ABSTRACT: In this study, we conducted a comprehensive multi-omics analysis, including proteomics, transcriptomics, and ubiquitinomics, to investigate the mechanism of PF-3758309 in HCT116 cells. Our results revealed that PF-3758309 promotes the degradation of RNA polymerase II subunit proteins (POLR2A/B/E) via the cullin-RING ligase pathway.

ORGANISM(S): Homo Sapiens

SUBMITTER: Minjia Tan

PROVIDER: PXD064705 | iProX | Thu Jun 05 00:00:00 BST 2025

REPOSITORIES: iProX

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Multi-omics analysis reveals RNA polymerase II degradation as a novel mechanism of PF-3758309's anti-tumor activity.

Jia Xinglong X Zhang Jingdan J Pan Lulu L He Jingliang J Zhu Mingrui M Zhao Lei L Zhang Xingyu X Zhao Wensi W Xie Dong D Shen Xiaoyan X Liu Bin B Tan Minjia M

Cell death discovery 20250825 1

PF-3758309, a pyrrolopyrimidine-based inhibitor of p21-activated kinase 4 (PAK4), has demonstrated preclinical anti-tumor activity. However, due to poor pharmacokinetics and off-target effects, it has not advanced to clinical use. In this study, we conducted a comprehensive multi-omics analysis, including proteomics, transcriptomics, and ubiquitinomics, to investigate the mechanism of PF-3758309 in HCT116 cells. Our results revealed that PF-3758309 promotes the degradation of RNA polymerase II s ...[more]

PMID: 40854914

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