9VS9

Small molecule 3-127 targeting YTHDC1

Summary for 9VS9

• Entry DOI: 10.2210/pdb9vs9/pdb
• Descriptor: YTH domain-containing protein 1, SULFATE ION, 2-chloranyl-~{N}-methyl-9~{H}-purin-6-amine, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 42858.20

Authors

Fu, S.,Wang, M.,Chen, S. (deposition date: 2025-07-08, release date: 2026-11-11)

Primary citation

Wang, M.,Fu, S.,Xu, Y.,Gao, J.,Ren, J.,Yang, X.,Xu, H.,Sun, G.,Li, Y.,Wang, Y.,Jin, L.,Chen, P.,Xu, Y.,Li, J.,Lin, H.,Hu, C.,Chen, K.,Xiong, H.,Luo, C.,Chen, S.
AS-TLC-Based High-Throughput Screening Integrated with CuAAC Optimization Strategy Facilitates the Rapid Discovery of YTHDC1 Inhibitor.
Adv Sci, :e77386-e77386, 2026

PubMed Abstract: The classical sequential workflow-individual compound screening, followed by stepwise design-synthesis-purification of derivatives-makes lead compound discovery time-consuming and cost-prohibitive. Herein, we developed Affinity Selection Thin-Layer Chromatography (AS-TLC) as a method for high-throughput screening (HTS), enabling efficient and cost-effective screening of compound mixtures. Furthermore, we integrated activity assays with AS-TLC to minimize target protein consumption and lower the false positive rate, through which we identified a YTH domain-containing protein 1 (YTHDC1) inhibitor, fragment YD, with a half-maximal inhibitory concentration (IC) of 20.01 ± 3.30 µm. Building on this hit, we applied copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry for rapid structural modification and compound library construction, ultimately obtaining LC-YD03 with significantly enhanced inhibitory activity (IC = 41.98 ± 6.24 nm). The interaction mode between LC-YD03 and YTHDC1 was further clarified via X-ray crystallographic analysis. This study demonstrates that the AS-TLC-activity assay platform enables efficient hit screening from compound mixtures; subsequent click chemistry-based combinatorial library technology accelerates lead compound optimization. Collectively, this workflow significantly reduces the time and cost associated with lead compound discovery.

PubMed: 42658481
DOI: 10.1002/advs.77386

Experimental method

X-RAY DIFFRACTION (1.82 Å)