A transferable perturbation proteomics framework for phenotype- 1 based annotation and antiproliferative potency scoring of antineoplastic agents
4 affiliations
- 1Wuya College of Innovation
- 2Shenyang Pharmaceutical University
- 3Institute of Digital Materia Medica and Structural Pharmacology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy
- 4Fujian University of Traditional Chinese Medicine
Abstract
Although antineoplastic agents target diverse proteins, whether they converge on conserved cellular response states remains unclear. Here, we generate a TMTpro 18-plex quantitative proteomics atlas of 367 antineoplastic agents in HepG2 cells and identify recurrent drug response phenotypes (DRPs). The higher-order organization of DRP is conserved across seven independent proteomic datasets and shows limited concordance with chemical structure and annotated mechanisms of action. Projection of 189 external profiles representing 94 compounds achieves 42.7% balanced reference-DRP recovery, a 3.8-fold enrichment above the permutation-derived baseline. DRPs also encode antiproliferative potency, enabling derivation of a six-protein Composite Proteomic Score (CPS-6; TBL1X, NAPA, PLEKHA7, ACSL1, ARL8B, and CCDC90B) that retains associations with relative antiproliferative potency across independent proteomic and transcriptomic datasets. Proteomic similarity further reveals phenotypic convergence among mechanistically distinct compounds and enables mechanism annotation of external compounds and natural products. An interactive portal enables projection of new perturbation proteomes for phenotype-based annotation and antiproliferative potency estimation. Together, our study establishes a transferable proteomic framework for antineoplastic agents, providing a scalable resource for mechanistic hypothesis generation, drug repositioning, and phenotype-guided drug discovery.
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BibTeX
@misc{liang2026transferable,
title = {{A transferable perturbation proteomics framework for phenotype- 1 based annotation and antiproliferative potency scoring of antineoplastic agents}},
author = {Jing Liang and Jundan Tian and Rui Zhang and Yueying Yang and Xu Cai and Pingping Wang and Meijing Wang and Zhiruo Zhang and Yuxin Gan and Yihan Ha and Disheng Feng and Hua Li and Lixia Chen},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15001038/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15001038/v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A transferable perturbation proteomics framework for phenotype- 1 based annotation and antiproliferative potency scoring of antineoplastic agents
AU - Jing Liang
AU - Jundan Tian
AU - Rui Zhang
AU - Yueying Yang
AU - Xu Cai
AU - Pingping Wang
AU - Meijing Wang
AU - Zhiruo Zhang
AU - Yuxin Gan
AU - Yihan Ha
AU - Disheng Feng
AU - Hua Li
AU - Lixia Chen
PY - 2026
DA - 2026/10/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15001038/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15001038/v2
AB - Although antineoplastic agents target diverse proteins, whether they converge on conserved cellular response states remains unclear. Here, we generate a TMTpro 18-plex quantitative proteomics atlas of 367 antineoplastic agents in HepG2 cells and identify recurrent drug response phenotypes (DRPs). The higher-order organization of DRP is conserved across seven independent proteomic datasets and shows limited concordance with chemical structure and annotated mechanisms of action. Projection of 189 external profiles representing 94 compounds achieves 42.7% balanced reference-DRP recovery, a 3.8-fold enrichment above the permutation-derived baseline. DRPs also encode antiproliferative potency, enabling derivation of a six-protein Composite Proteomic Score (CPS-6; TBL1X, NAPA, PLEKHA7, ACSL1, ARL8B, and CCDC90B) that retains associations with relative antiproliferative potency across independent proteomic and transcriptomic datasets. Proteomic similarity further reveals phenotypic convergence among mechanistically distinct compounds and enables mechanism annotation of external compounds and natural products. An interactive portal enables projection of new perturbation proteomes for phenotype-based annotation and antiproliferative potency estimation. Together, our study establishes a transferable proteomic framework for antineoplastic agents, providing a scalable resource for mechanistic hypothesis generation, drug repositioning, and phenotype-guided drug discovery.
ER -