TNG908 is a MTAP (methylthioadenosine phosphorylase)-synergistic inhibitor of PRMT5 (protein arginine methyltransferase 5). It is orally active and capable of crossing the blood–brain barrier, making it suitable for targeting both systemic and central nervous system tumors. TNG908 selectively exploits MTAP deletion—a common alteration in cancers—to enhance its antitumor efficacy, making it a promising agent for cancer research and precision oncology.
TNG908 is a MTAP (methylthioadenosine phosphorylase)-synergistic inhibitor of PRMT5 (protein arginine methyltransferase 5). It is orally active and capable of crossing the blood–brain barrier, making it suitable for targeting both systemic and central nervous system tumors. TNG908 selectively exploits MTAP deletion—a common alteration in cancers—to enhance its antitumor efficacy, making it a promising agent for cancer research and precision oncology.
In Vitro
Ralometostat demonstrates selective growth inhibition in MTAP-deleted cell lines relative to MTAP wild-type controls. In MTAP-isogenic HCT116 colorectal cancer models, reported cellular potency was approximately 0.13 μM in MTAP-null cells versus ~3.1 μM in MTAP WT cells [1]. Dose-dependent reduction of SDMA confirms on-target activity [1,2]. Activity has been reported in MTAP-deleted models including colorectal cancer, glioblastoma, NSCLC, and malignant peripheral nerve sheath tumor (MPNST) [2,3].
In Vivo
Oral administration produces dose-dependent antitumor activity in multiple MTAP-deleted CDX and PDX models:
LN18 (GBM) CDX – 10–60 mg/kg BID; up to 100% tumor growth inhibition at 60 mg/kg [1]
Antitumor efficacy correlates with sustained PRMT5 pathway suppression in tumor tissue (SDMA reduction) [1,2].
References
[1] Cottrell KM et al. Discovery of TNG908: A Selective, Brain-Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers. J Med Chem. 2024. DOI: 10.1021/acs.jmedchem.4c00133
[2] Briggs KJ et al. TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers. 2025. PMID: 39756156
[3] Zhang X et al. MTA-Cooperative PRMT5 Inhibitors Are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models. Clin Cancer Res. 2025;31:4779–4789. DOI: 10.1158/1078-0432.CCR-24-3610
Store lyophilized at -20ºC, keep desiccated. In lyophilized form, the chemical is stable for 36 months. In solution, store at -20ºC and use within 1 months to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.
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