Evidence map›Paper›PMID 40854914›Full record

ArticleCell death discovery2025

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

Xinglong Jia, Jingdan Zhang, Lulu Pan, Jingliang He, Mingrui Zhu, Lei Zhao, Xingyu Zhang, Wensi Zhao, Dong Xie, Xiaoyan Shen and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Xinglong Jia *School of Pharmacy, Fudan University, Shanghai, China.
Jingdan Zhang *School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Lulu Pan *Department of Pharmacy, Central China Fuwai Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Jingliang He *Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
Mingrui ZhuState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Lei ZhaoTranslational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, and Cancer Center, School of Medicine, Tongji University, Shanghai, China.
Xingyu ZhangJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
Wensi ZhaoDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Dong XieDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Xiaoyan ShenSchool of Pharmacy, Fudan University, Shanghai, China. shxiaoy@fudan.edu.cn.ORCID http://orcid.org/0000-0003-4828-3268
Bin LiuJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China. liubin@jou.edu.cn.ORCID http://orcid.org/0000-0003-1569-2604
Minjia TanState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mjtan@simm.ac.cn.ORCID http://orcid.org/0000-0002-6784-9653

Funding

National Natural Science Foundation of China (National Science Foundation of China) 22225702National Natural Science Foundation of China (National Science Foundation of China) 82273167National Natural Science Foundation of China (National Science Foundation of China) U24A20524
6 · The paper itself

Abstract

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 subunit proteins (POLR2A/B/E) via the cullin-RING ligase pathway. This process is mediated by the E3 ubiquitin ligase DNA damage-binding protein 2 (DDB2), and is independent of PAK4. Furthermore, the small-molecule inhibitor MLN4924, which blocks NEDD8-activating enzyme, reversed the degradation of POLR2A/B/E, supporting the role of ubiquitin-proteasome pathways in this process. Functional assays confirmed that PF-3758309 inhibits tumor cell growth and migration by promoting ubiquitination-dependent degradation of POLR2A/B/E. These findings uncover a previously unrecognized mechanism of PF-3758309's anti-tumor activity and provide a basis for further investigation into its therapeutic potential.

Identifiers

PMID40854914
PMCPMC12379277

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.