Discovery of a small molecule RIOK1 inhibitor CINS-1 against colorectal cancer via disrupting ribosomal biosynthesis.
- 1Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
- 2NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Department of Pharmacy, Pingshan Hospital, Southern Medical University, Shenzhen 518100, China.
Abstract
Colorectal cancer (CRC) remains one of the most prevalent malignancies globally. Despite significant advancements in targeted therapies, drug resistance and therapeutic target mutations continue to pose challenges. Consequently, identifying novel therapeutic targets and developing related compounds are essential for discovering new CRC treatment strategies. The RIO Kinase 1 (RIOK1) protein has emerged as a potential anti-tumor target, playing a critical role in eukaryotic ribosomal biosynthesis and modulating cellular proliferation. However, few compounds have been designed to target RIOK1, and the antitumor activity of RIOK1 inhibitors has yet to be thoroughly investigated. In this study, we report the optimization of pyridine caffeic acid benzyl amide derivatives as RIOK1 inhibitors and identified CINS-1 as a potent compound with markedly enhanced binding affinity for AfRIOK1 and RIOK1. Notably, we elucidated the crystal structure of AfRIOK1 in complex with CINS-1. Our findings further confirm the inhibitory effects of CINS-1 on CRC cell proliferation both in vitro and in vivo. Additionally, CINS-1 was shown to disrupt ribosomal biosynthesis by hindering 18S maturation and triggering a P53-mediated nucleolar stress response. Overall, these results provide a theoretical and empirical basis for considering the RIOK1 inhibitor CINS-1 as a promising candidate for anti-CRC therapy.
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BibTeX
@article{jiang2026discovery,
title = {{Discovery of a small molecule RIOK1 inhibitor CINS-1 against colorectal cancer via disrupting ribosomal biosynthesis.}},
author = {Ying Jiang and Chuan Huang and Fang Wu and Guolong Liu and Shanhe Wan and Yongxin Chen and Ruohong Yan and Zichao Yang and Yuanxin Tian and Tingting Zhang and Xiaoyun Wu and Le Yu and Shaoyu Wu and Shuwen Liu and Jianjun Chen and Wei Xu and Jiajie Zhang},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jul,
doi = {10.1016/j.apsb.2026.07.004},
url = {https://europepmc.org/article/MED/42948403},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Discovery of a small molecule RIOK1 inhibitor CINS-1 against colorectal cancer via disrupting ribosomal biosynthesis.
AU - Ying Jiang
AU - Chuan Huang
AU - Fang Wu
AU - Guolong Liu
AU - Shanhe Wan
AU - Yongxin Chen
AU - Ruohong Yan
AU - Zichao Yang
AU - Yuanxin Tian
AU - Tingting Zhang
AU - Xiaoyun Wu
AU - Le Yu
AU - Shaoyu Wu
AU - Shuwen Liu
AU - Jianjun Chen
AU - Wei Xu
AU - Jiajie Zhang
PY - 2026
DA - 2026/07/08
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.07.004
UR - https://europepmc.org/article/MED/42948403
AB - Colorectal cancer (CRC) remains one of the most prevalent malignancies globally. Despite significant advancements in targeted therapies, drug resistance and therapeutic target mutations continue to pose challenges. Consequently, identifying novel therapeutic targets and developing related compounds are essential for discovering new CRC treatment strategies. The RIO Kinase 1 (RIOK1) protein has emerged as a potential anti-tumor target, playing a critical role in eukaryotic ribosomal biosynthesis and modulating cellular proliferation. However, few compounds have been designed to target RIOK1, and the antitumor activity of RIOK1 inhibitors has yet to be thoroughly investigated. In this study, we report the optimization of pyridine caffeic acid benzyl amide derivatives as RIOK1 inhibitors and identified CINS-1 as a potent compound with markedly enhanced binding affinity for AfRIOK1 and RIOK1. Notably, we elucidated the crystal structure of AfRIOK1 in complex with CINS-1. Our findings further confirm the inhibitory effects of CINS-1 on CRC cell proliferation both in vitro and in vivo. Additionally, CINS-1 was shown to disrupt ribosomal biosynthesis by hindering 18S maturation and triggering a P53-mediated nucleolar stress response. Overall, these results provide a theoretical and empirical basis for considering the RIOK1 inhibitor CINS-1 as a promising candidate for anti-CRC therapy.
SN - 2211-3835
SN - 2211-3843
ER -