Matias-Barrios Victor M, Radaeva Mariia, Rosellinny Graciella, Jia Qiongqiong, Xie Ning, Villanueva Monica, Ibrahim Hanadi, Smith Jason, Gleave Martin, Lallous Nada, Straus Suzana K, Cherkasov Artem, Dong Xuesen
The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
Cell Death Discov. 2025 Jan 12;11(1):5. doi: 10.1038/s41420-024-02281-z.
Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.
Lin28是癌症干细胞基因网络的关键调节因子，可促进多种肿瘤中抗治疗性肿瘤进展。然而，尚无Lin28抑制剂被批准用于治疗癌症患者，这促使人们探索新型化合物作为临床试验的候选药物进行测试。在本研究中，我们将计算机辅助药物设计（CADD）与定量生化和生物学分析相结合。这些努力导致发现了Ln268作为一种候选药物，它可以阻止Lin28与其RNA底物结合并抑制Lin28活性。Ln268抑制了Lin28介导的癌细胞增殖和球体生长。核磁共振光谱结果证实，Ln268扰乱了Lin28锌指结构域的构象，验证了CADD的合理药物设计。Ln268的抑制作用取决于癌细胞中Lin28蛋白的表达，突出了Ln268有限的脱靶效应。此外，Ln268与几种化疗药物协同作用以抑制肿瘤细胞生长。总之，Ln268是作为癌症治疗靶向Lin28的有前景的进一步开发候选药物。
