Ralometostat

CAS 2760481-53-4

MF C21H23N5O2S MW409.51

(2R,5S)-N-(6-Amino-5-methyl-3-pyridinyl)-2-(5-benzothiazolyl)-5-methyl-α-oxo-1-piperidineacetamide

1-Piperidineacetamide, N-(6-amino-5-methyl-3-pyridinyl)-2-(5-benzothiazolyl)-5-methyl-α-oxo-, (2R,5S)-

N-(6-amino-5-methylpyridin-3-yl)-2-[(2R,5S)-2-(1,3-benzothiazol -5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide

N-(6-amino-5-methylpyridin-3-yl)-2-[(2R,5S)-2-(1,3-benzothiazol -5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide
antineoplastic, TNG908, TNG 908, X7CRL5YNN5

Ralometostat (also known as TNG908) is an experimental, orally active oncology drug designed to treat advanced or metastatic solid tumors. It is classified as a potent, brain-penetrant, and selective methylthioadenosine (MTA)-cooperative PRMT5 inhibitor.

Developed by Tango Therapeutics, the drug targets specific genetic deletions frequently found in various human cancers.

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Mechanism of Action

Ralometostat relies on a concept called synthetic lethality.

• Target Deletion: It targets cancers that have a deletion of the methylthioadenosine phosphorylase (MTAP) gene. This deletion occurs in roughly 10% to 15% of all human cancers.
• The “Trap”: When the MTAP gene is missing, a metabolite called MTA builds up heavily inside the tumor cells.
• Selective Killing: Ralometostat specifically binds to this PRMT5•MTA complex. This enables it to selectively kill MTAP-deleted cancer cells while sparing normal, healthy tissues.

This targeted approach bypasses the severe bone marrow toxicities caused by older, non-selective first-generation PRMT5 inhibitors.

Key Clinical Features

• Blood-Brain Barrier Penetration: The drug is chemically optimized to cross the blood-brain barrier. This makes it highly effective in evaluating tumors within the central nervous system (CNS).
• Therapeutic Targets: It is studied in clinical oncology settings for several tumor types, including:
  • Glioblastoma (GBM) and brain metastases.
  • Non-small cell lung cancer (NSCLC).
  • Malignant peripheral nerve sheath tumors (MPNST) and soft tissue sarcomas.
  • Urothelial carcinoma and cholangiocarcinoma.
  • Safety and Tolerability of TNG908 in Patients With MTAP-deleted Solid TumorsCTID:
  • NCT05275478
  • Phase:
  • Phase 1/Phase 2
  • Status:
  • Terminated
  • Date:
  • 2026-04-15

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Chemical & Trial Profile

Development Phase: Evaluated in Phase I/II clinical trials (such as NCT05275478) as a standalone precision therapy and in combination with other targeted inhibitors

Ralometostat is an orally available small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration, ralometostat selectively binds to PRMT5 and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is overexpressed in several neoplasms and is essential for the viability of cancer and normal cells. Elevated levels are associated with decreased patient survival. Methylthioadenosine phosphorylase (MTAP) is deleted in certain cancer cells leading to an accumulation of methylthioadenosine (MTA). As MTA binds to and partially inhibits PRMT5, MTAP-null cancer cells are specifically sensitive to PRMT5 inhibitors. This may spare normal, healthy cells that are without MTAP-deletions and lower systemic toxicity.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US358600101&_cid=P11-MSTR3S-83508-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US399951504&_cid=P11-MSTR3S-83508-1

Example 1. The synthesis of N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound (I)) and N-(6-amino-5-methylpyridin-3-yl)-2-((2S,5R)-2-(benzo [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound (Ia))

The enantiomers were separated by chiral HPLC (column: IC II, Hexane-IPA-MeOH, 50-25-25, 12 ml/min as mobile phase) to give the two individual enantiomers Compound (Ia)N-(6-amino-5-methylpyridin-3-yl)-2-((2 S, 5R)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (161 mg, 393.16 μmol, 97.28% yield) RetTime=32.4 min, [α]21D=−176.7°(c=0.1 g/100 mL, EtOH) and Compound (I)N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (160 mg, 390.72 μmol, 96.68% yield) RetTime=45.8 min, [α]21D=+191.5° (c=0.1 g/100 mL, EtOH).

Compound (I): RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)=47.098 min.

1H NMR (600 MHz, DMSO-d6) δ 0.98-1.06 (m, 3H), 1.30-1.42 (m, 1H), 1.66-1.75 (m, 1H), 1.82-1.91 (m, 1H), 1.95-2.04 (m, 3H), 2.06-2.23 (m, 1H), 2.26-2.35 (m, 1H), 2.76-3.27 (m, 1H), 3.38-4.06 (m, 1H), 5.26-5.60 (m, 1H), 5.60-5.76 (m, 2H), 7.39-7.46 (m, 1H), 7.50 (s, 1H), 7.92-8.01 (m, 1H), 8.01-8.06 (m, 1H), 8.13-8.20 (m, 1H), 9.37-9.43 (m, 1H), 10.50-10.70 (m, 1H).

LCMS(ESI): [M+H] + m/z: calcd 409.2; found 410.0; Rt=1.992 min.

Compound (Ia) RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)=35.176 min.

1H NMR (600 MHz, DMSO-d6) δ 1.00-1.05 (m, 3H), 1.27-1.40 (m, 1H), 1.64-1.75 (m, 1H), 1.82-1.93 (m, 1H), 1.95-2.04 (m, 3H), 2.07-2.25 (m, 1H), 2.27-2.35 (m, 1H), 2.75-3.27 (m, 1H), 3.42-4.11 (m, 1H), 5.28-5.59 (m, 1H), 5.60-5.74 (m, 2H), 7.40-7.45 (m, 1H), 7.49 (s, 1H), 7.94-8.01 (m, 1H), 8.01-8.06 (m, 1H), 8.13-8.19 (m, 1H), 9.36-9.42 (m, 1H), 10.52-10.58 (m, 1H).

LCMS(ESI): [M+H] + m/z: calcd 409.2; found 410.2; Rt=2.001 min.

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References

• Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted CancersPublication Name:Journal of Medicinal ChemistryPublication Date:2024-04-10PMCID:PMC11056935PMID:38595098DOI:10.1021/acs.jmedchem.4c00133
• [Intracellular protein breakdown. VI. Isolation, properties and biological significance of cathepsin D from rat liver]Publication Name:Acta biologica et medica GermanicaPublication Date:1976PMID:9765

PAT

Piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful for the treatment of MTAP-deficient and/or MTA-accumulating cancersPublication Number:

KR-20230094196-APriority Date:

2020-07-31

• Compounds and methods of usePublication Number:US-2023113778-A1Priority Date:2020-07-31
• Piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful in the treatment of MTAP deficiency and/or MTA accumulation cancersPublication Number:CN-116568677-APriority Date:2020-07-31
• Compounds and methods of usePublication Number:US-11999727-B2Priority Date:2020-07-31Grant Date:2024-06-04
• Compounds and methods of usePublication Number:US-2022127256-A1Priority Date:2020-07-31
• Compounds and methods of usePublication Number:US-12264154-B2Priority Date:2020-07-31Grant Date:2025-04-01
• Crystalline form of n-(6-amino-5-methylpyridin-3-yl)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide, pharmaceutical compositions and methods of use thereofPublication Number:EP-4448517-A1Priority Date:2021-12-17
• Compounds and methods of usePublication Number:US-2024279219-A1Priority Date:2020-07-31
• Compounds and methods of usePublication Number:US-2024228478-A1Priority Date:2020-07-31
• Compounds and methods of usePublication Number:US-11492350-B2Priority Date:2020-07-31Grant Date:2022-11-08
• Piperidin-1-yl-n-pyrydine-3-yl-2-oxoacetamide derivatives useful for the treatment of mtap-deficient and/or mta-accumulating cancersPublication Number:EP-4188920-A1Priority Date:2020-07-31
• Prmt5 inhibitors for use in methods of treating mta-accumulating cancerPublication Number:WO-2025217297-A1Priority Date:2024-04-09
• Prmt5 inhibitor for use in cancer therapyPublication Number:WO-2024170488-A1Priority Date:2023-02-13
• Methods of treatment of cancerPublication Number:TW-202423435-APriority Date:2022-08-15
• MTA synergizes with PRMT5 inhibitors for cancer treatmentPublication Number:CN-119730853-APriority Date:2022-08-15
• Mta-cooperative prmt5 inhibitors for use in the treatment of cancerPublication Number:WO-2024038004-A1Priority Date:2022-08-15

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