TNG462

Overview

TNG462 is an oral, investigational, MTA‑cooperative PRMT5 inhibitor being developed by Tango Therapeutics for solid tumors with homozygous MTAP loss (occurs in roughly 10–15% of cancers). It entered a phase 1/2 first‑in‑human trial in July 2023 (NCT05732831), and a separate phase 1/2 combination trial in RAS‑mutant, MTAP‑deleted pancreatic and lung cancers began dosing in June 2025 (NCT06922591). The FDA previously granted Fast Track designation to TNG462. ClinicalTrials.gov listing (Dana‑Farber) Company trial start release Combo‑trial announcement (dana-farber.org)

Mechanism of action

• Target: PRMT5, a type II arginine methyltransferase that catalyzes symmetric dimethylation (SDMA) on protein substrates.
• Mechanism: “MTA‑cooperative” PRMT5 inhibition. In MTAP‑deleted tumors, the metabolite methylthioadenosine (MTA) accumulates and binds the PRMT5 cofactor site, creating a hypomorphic PRMT5 state. TNG462 is designed to preferentially inhibit the PRMT5•MTA complex, enabling tumor‑selective activity while sparing normal tissues. J Med Chem – TNG462 discovery J Med Chem – mechanism design review Science 2016 – MTAP–PRMT5 dependency (pubs.acs.org)

Preclinical data show TNG462 has enhanced potency and MTAP‑selectivity versus earlier PRMT5 inhibitors and supports combinations with KRAS or EGFR inhibitors. AACR 2023 abstract AACR 2025 abstract (combinations) (aacrjournals.org)

Efficacy

Human efficacy data are preliminary and based on company disclosures from the ongoing phase 1/2 monotherapy trial:

• As of an October 20, 2024 data cutoff: 59 patients enrolled; 39 were evaluable at active doses (160–300 mg once daily). Confirmed RECIST partial responses have been observed across multiple tumor types (including NSCLC and pancreatic), with a median time to response of 16 weeks. In a small cholangiocarcinoma subset, 3/7 patients had confirmed partial responses (ORR 43%); several patients remained on therapy beyond 24 weeks at the time of reporting. Company update, Nov 6, 2024 Business Wire copy of same release (ir.tangotx.com)

• In the dose‑escalation cohort, the company’s 2024 Form 10‑K reports a median PFS of 24 weeks in evaluable patients at active doses (preliminary, non–peer‑reviewed). SEC filing (TNGX 10‑K) (sec.gov)

No peer‑reviewed clinical efficacy publication is yet available as of October 7, 2025. Additional monotherapy data are expected in 2H 2025 per company guidance. Q1 2025 update (ir.tangotx.com)

Safety

Early, non–peer‑reviewed safety data from the phase 1/2 monotherapy trial indicate:

• Overall well tolerated at active doses (200–300 mg QD under evaluation); thrombocytopenia has been the dose‑limiting toxicity. Common class‑related adverse events (nausea, vomiting, diarrhea, fatigue) were mostly grade 1 and occurred in <20% of patients; dysgeusia was not reported at expansion doses. Company update, Nov 6, 2024 Investor materials/SEC exhibit with dose info (ir.tangotx.com)

Formal, peer‑reviewed safety results in humans have not yet been published.

Ongoing clinical studies

• Monotherapy (first‑in‑human): Phase 1/2, open‑label, dose escalation/expansion in MTAP‑deleted solid tumors; includes a pembrolizumab combination arm. NCT05732831. Dana‑Farber listing Stanford listing (dana-farber.org)
• Combinations in RAS‑mutant disease: Phase 1/2 trial of TNG462 with daraxonrasib (RMC‑6236) or zoldonrasib (RMC‑9805) in MTAP‑deleted, RAS‑mutant pancreatic or lung cancer. NCT06922591. First patient dosed June 27, 2025. Dana‑Farber listing Company announcement (dana-farber.org)

Further reading

• Peer‑reviewed medicinal chemistry describing TNG462: Discovery of TNG462 (J Med Chem, 2025). (pubs.acs.org)
• Mechanistic context for MTA‑cooperative PRMT5 inhibition: Mechanism switching to MTA‑cooperative PRMT5 inhibitors (J Med Chem, 2025). (pubs.acs.org)
• Foundational biology: MTAP deletion creates dependence on PRMT5 (Science, 2016). (science.org)
• Preclinical combinations: AACR 2025 abstract on TNG462 + KRAS/EGFR inhibitors. (aacrjournals.org)
• Clinical trial registry/info: NCT05732831 monotherapy; NCT06922591 combinations. (dana-farber.org)

Notes: Human efficacy and safety information above comes from company communications and SEC filings from November 2024–June 2025 and should be considered preliminary until presented at a scientific meeting with clinical data or published in a peer‑reviewed journal. Company update (Nov 6, 2024) SEC filing. (ir.tangotx.com)

Last updated: Oct 2025