Work

Discovery of a small molecule RIOK1 inhibitor CINS-1 against colorectal cancer via disrupting ribosomal biosynthesis

Year: 2026

Type: article

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.

Source: Acta Pharmaceutica Sinica B

DOI: 10.1016/j.apsb.2026.07.004