Discovery, evaluation and mechanism study of WDR5-targeted small molecular inhibitors for neuroblastoma

Qi-lei Han1, Xiang-lei Zhang2, Peng-xuan Ren2,3, Liang-he Mei4, Wei-hong Lin1, Lin Wang2,3, Yu Cao2,3, Kai Li1, Fang Bai2,3,5,6
1 Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai 201102, China
2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
3 School of Information Science and Technology, ShanghaiTech University, Shanghai 201210, China
4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
6 Shanghai Clinical Research and Trial Center, Shanghai 201210, China
Correspondence to: Kai Li:, Fang Bai:,
DOI: 10.1038/s41401-022-00999-z
Received: 21 June 2022
Accepted: 12 September 2022
Advance online: 7 October 2022


Neuroblastoma is the most common and deadliest tumor in infancy. WDR5 (WD Repeat Domain 5), a critical factor supporting an N-myc transcriptional complex via its WBM site and interacting with chromosome via its WIN site, promotes the progression of neuroblastoma, thus making it a potential anti-neuroblastoma drug target. So far, a few WIN site inhibitors have been reported, and the WBM site disruptors are rare to see. In this study we conducted virtual screening to identify candidate hit compounds targeting the WBM site of WDR5. As a result, 60 compounds were selected as candidate WBM site inhibitors. Cell proliferation assay demonstrated 6 structurally distinct WBM site inhibitors, numbering as compounds 4, 7, 11, 13, 19 and 22, which potently suppressed 3 neuroblastoma cell lines (MYCN-amplified IMR32 and LAN5 cell lines, and MYCN-unamplified SK-N-AS cell line). Among them, compound 19 suppressed the proliferation of IMR32 and LAN5 cells with EC50 values of 12.34 and 14.89 μM, respectively, and exerted a moderate inhibition on SK-N-AS cells, without affecting HEK293T cells at 20 μM. Analysis of high-resolution crystal complex structure of compound 19 against WDR5 revealed that it competitively occupied the hydrophobic pocket where V264 was located, which might disrupt the interaction of MYC with WDR5 and further MYC-medicated gene transcription. By performing RNA-seq analysis we demonstrated the differences in molecular action mechanisms of the compound 19 and a WIN site inhibitor OICR-9429. Most interestingly, we established the particularly high synergy rate by combining WBM site inhibitor 19 and the WIN site inhibitor OICR-9429, providing a novel therapeutic avenue for neuroblastoma.

Keywords: neuroblastoma; WDR5; WBM site; protein-protein interaction interrupters; drug combination therapy

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