RBM39 degrader anticancer activity against neuroblastoma: CDKN2A/B deletion as a biomarker
Presenter: Dan Lu, MS Session: Proximity-Induced Drug Discovery 2 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
James Finn 1 , Imad salhab 2 , Haihong Jin 3 , Fei Liu 1 , Dong Liu 1 , Yunkai Zhang 1 , Xing Liu 4 , James Tonra 1 , Lan Huang 1 , Dan Lu 1 1 Seed Therapeutics, King of Prussia, PA, 2 Seed Therapeutics, New York, NY, 3 Vitsgen Therapeutics, Portland, OR, 4 Independent Consultor, King of Prussia, PA
Abstract
Robust anticancer effects of molecular glue RBM39 degraders have been reported in human neuroblastoma models (DOI: 10.1126/sciadv.abj5405 and 10.1038/s41467-022-28907-3). In the present study we further explored the MOA underlying the potent activity of RBM39 degraders in neuroblastoma, utilizing SEED Therapeutics’ optimized RBM39 degrader ST-00937, and its deuterium derivative ST-01156 that was recently cleared by the FDA for clinical testing (NCT07197554 ) . Method In vitro anticancer activity was profiled in 3D clonogenic assays utilizing tissue derived from 4 neuroblastoma patients and 6 human neuroblastoma tumor cell lines. In vivo anticancer efficacy was evaluated in nude mice bearing subcutaneous tumors established with SH-SY5Y human neuroblastoma cells. Cell lysates generated from 2D culture of neuroblastoma cell lines treated with ST-01156 were evaluated by TMT labeling mass spectrometry and Western Blot. Result ST-00937 treatment showed differential anticancer activity in 6 neuroblastoma cell lines and 4 patient-derived models. For the 6 neuroblastoma cell lines, the IC 50 values ranged from 0.04 to 0.3µM among 5 sensitive cell lines, while SH-EP cells did not respond. The IC 50 for colony formation ranged from 0.03 to 2.3µm in 4 patient-derived models. Notably, the most insensitive patient-derived model NB0277 has a homozygous CDKN2A/B deletion. In vitro activity was extended to in vivo activity utilizing SH-SY5Y cells. In vivo, complete tumor regressions were observed with 5-Days On/2-Days Off, twice daily oral treatment with ST-01156, without body weight loss. Proteomic analysis in vitro showed that ST-01156 decreased proteins involved in DNA damage and cell cycle control, and increased p53 signaling after 16h treatment. The divergent anticancer responses of SH-SY5Y and SH-EP subclones (both derived from SK-N-SH) warranted further investigation. Although both lines expressed similar levels of RBM39 and exhibited complete RBM39 degradation after treatment, distinct downstream effects were observed. In SH-SY5Y cells (adrenergic CDKN2A wild-type, cMYC amplified), cMYC expression was downregulated and the p21/p53 pathway was upregulated by ST-01156. In contrast, these changes were not detected in SH-EP cells (mesenchymal, CDKN2A/B deletion). This differential regulation may explain why cleaved caspase-3 (apoptosis) was not observed in ST-01156 treated SH-EP CDKN2A/B deleted cells, although DNA damage indicated by γH2AX was increased in both cell lines. Conclusion RBM39 degraders demonstrate differential potency in 6 neuroblastoma cell lines and 4 patient-derived models in vitro, and total tumor regression in SH-SY5Y in vivo. DNA damage and increased p53-mediated apoptosis are confirmed in the sensitive neuroblastoma model SH-SY5Y, while resistance in CDKN2A/B-deleted lines suggests CDKN2A loss may serve as a predictive biomarker of resistance to RBM39-targed therapy.
Disclosure
J. Finn, Seed therapeutics Employment. I. salhab, seed therapeutics Employment. F. Liu, Seed Therapeutics Employment. D. Liu, Seed Therapeutics Employment. Y. Zhang, seed therapeutics Employment. X. Liu, Seed therapeutics Employment, Other, former Seed employee (ended April 2025). J. Tonra, seed therapeutics Employment. L. Huang, seed therapeutics Employment. Beyond Spring Employment. D. Lu, Seed Therapeutics Employment.
Cited in
Control: 6129 · Presentation Id: 8738 · Meeting 21436