June 2026

The protein arginine methyltransferase 5 (PRMT5) field is actively evolving - with clinical setbacks alongside promising advances, reflecting both the complexity of the target and its continued relevance in oncology.

Several developments from early 2026 illustrate this dynamic:

Discontinued small-molecule program: Following modest clinical results, Amgen announced the termination of its entire AMG 193 (PRMT5 molecular glue inhibitor) development program, including four ongoing clinical trials. This suggests that PRMT5 remains a challenging therapeutic target.
Positive news from novel clinical trials: At the beginning of this month, AstraZeneca reported encouraging Phase 1 results for its selective PRMT5 inhibitor AZD3470 as monotherapy in relapsed/refractory classical Hodgkin lymphoma. This reflects a broader exploration of PRMT5 inhibition beyond solid tumors. AZD3470 discovery is described in the company’s recent publication.
Next-generation therapies advancing: Tango Therapeutics initiated a Phase 1/2 trial for TNG456, a highly potent, selective, and brain-penetrant PRMT5 inhibitor. It is designed for a new treatment of glioblastoma, an area of significant unmet need. The compound represents Tango's third PRMT5 asset to enter the clinic, highlighting the company's sustained commitment to this target.

The development of Tango’s TNG456 is particularly interesting: after an earlier brain-penetrant compound (TNG908) was discontinued in 2024 due to insufficient CNS exposure, the company redesigned its approach. What key structural and optimization moves enabled the successful discovery of the new promising compound?

Structure-guided insights for TNG456’s potency, selectivity, and brain penetrance

PRMT5 is a type II protein arginine methyltransferase involved in key cellular processes, including tumor cell proliferation and differentiation. Its therapeutic relevance is heightened in cancers with MTAP (methylthioadenosine phosphorylase) gene deletion, which represents one of the largest precision-oncology populations. MTAP deletion is present in around 10% to 15% of all human cancers, of which 45% are glioblastomas (aggressive brain tumors). This makes PRMT5 a high-value target for drug discovery.

In MTAP-deleted cancer cells, the metabolite MTA (5′‑methylthioadenosine) accumulates and competes with PRMT5's natural cofactor SAM, creating a tumor-specific vulnerability. Tango's MTA-cooperative inhibitors exploit this selectivity, aiming for potent tumor suppression with improved tolerability compared to first-generation, non-selective PRMT5 inhibitors.

Building on their work with two earlier compounds (TNG908 and vopimetostat), Tango's scientists optimized the series to achieve brain penetrance, crucial for CNS-related cancers, while maintaining potency, selectivity, and favorable drug-like properties. The resulting compound, TNG456, shows an average 55× selectivity for MTAP-deleted cells compared to MTAP wild-type counterparts in preclinical assays.

Tango’s paper on the TNG456 discovery was published last month (May 2026) and describes the structure-guided optimization strategy that underlies it.

Key structural insights that aided the medicinal chemistry hypothesis include:

Validation of acyclic scaffolds as effective bioisosteres: Scientists confirmed that acyclic analogs can act as bioisosteres for the piperidine ring — previously used in earlier PRMT5 inhibitors (TNG908 and vopimetostat). They occupy the same space in the PRMT5–MTA active site. This insight was not apparent from 2D chemical representations alone; therefore, the crucial 3D structural analysis confirmed a viable starting point for the development of TNG456.

Distinct binding mode of acyclic analogs: The co-crystal structure of TNG456 bound to PRMT5–MTA yielded crucial new insights into how acyclic analogs interact with the active site, including:
- Rearrangement of the binding pocket: The benzylic group of TNG456 adopts a flipped orientation compared to the aromatic substituents in the piperidine series, engaging in π-stacking interactions with key residues (Phe580 and Tyr304).

Formation of a new sub-pocket: The TNG456’s CF₃ group fills a sub-pocket created by movement of a nearby α-helix (residues 296-301), which rearranges to accommodate the benzylic substituent. The new pocket is created by the repositioning of Phe300, Tyr297, and Phe577.

TNG456 (green PDB 9ZL4) in the PRMT5–MTA active site, showing the newly formed sub-pocket (green surface). The CF₃ group extends into a pocket created by rearrangement of a nearby α-helix — a feature not accessible with earlier piperidine-based inhibitors.
*Image is produced with the* *3decision®* *software*.

Conclusion

In the pursuit of next-generation MTA-cooperative PRMT5 inhibitors for CNS-related tumors, Tango's scientists combined medicinal chemistry strategies with structural insights to develop TNG456, a highly potent, selective, and brain-penetrant compound, now in Phase 1/2 clinical trials.

These efforts illustrate how structure-guided optimization can address the challenges of a biologically compelling but difficult target — and suggest that the PRMT5 field continues to advance through increasingly rational drug design.

Reference:

Cottrell, Kevin M et al. “Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.” Journal of medicinal chemistry vol. 67,8 (2024): 6064-6080. doi:10.1021/acs.jmedchem.4c00133

Structural exploration of the reference paper and images is produced using the 3decision software.

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PRMT5

June 2026

Structure-guided insights for TNG456’s potency, selectivity, and brain penetrance

Conclusion

Reference:

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