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TH9619
MTHFD1/2 enzyme inhibitor; cellular folate-trapping mechanism
Evidence Score
22
TH9619 inhibits the dehydrogenase/cyclohydrolase activities of MTHFD1 and MTHFD2 in biochemical assays. In cancer-cell models, Green et al. (Nat Metab 2023, PMID 37012496) found inhibition of MTHFD1 and nuclear MTHFD2, but not mitochondrial MTHFD2. Continued mitochondrial formate release combined with MTHFD1 inhibition caused accumulation of 10-formyl-THF (folate trapping), thymidylate depletion and cell death in MTHFD2-expressing cancer cells; physiological hypoxanthine enhanced this effect. This is not a simple blockade of mitochondrial one-carbon output. Manolakou et al. (PMID 42270592) reported TH9619 activity in rheumatoid-arthritis T cells and arthritis models, not SDH-deficient cancer. ClinicalTrials.gov lists NCT07151040 as a recruiting first-in-human Phase 1/2 study in advanced cancer, with actual start August 22, 2025; enrollment does not establish efficacy or SDH-specific benefit. SDH applicability is an unvalidated hypothesis: Hart et al. (PMID 42082831) established succinate-mediated ATCase inhibition and pyrimidine insufficiency in SDH-deficiency models, not MTHFD2 upregulation, one-carbon dependency or selective TH9619 sensitivity. No SDH-specific TH9619 result was verified in this review. The inferred combination with SDH-driven nucleotide stress and any synergy with DHODH inhibitors require direct testing. This entry is a research lead, not a treatment recommendation.
Unvalidated research hypothesis: metabolic stress after SDH loss may create a one-carbon metabolism vulnerability. SDH-specific MTHFD2 dependency is not established by the sources checked for the October 7 drug-identity correction. The former LY3410738 pairing was incorrect: LY3410738 inhibits mutant IDH1/IDH2, not MTHFD2/MTHFD1L (PMID 41026608; NCT04521686). TH9619 is a verified MTHFD1/2 biochemical inhibitor and clinical-stage research lead, but cellular mitochondrial MTHFD2 inhibition was not observed in the primary cancer study (PMID 37012496). SDH-specific TH9619 sensitivity remains unvalidated; drug identity is not proof of this dependency.
Upstream event:
Hypothesis only: SDH loss and metabolic stress may alter one-carbon metabolism; the proposed MTHFD2 dependency requires direct SDH-specific validation.
Downstream effects:
MTHFD2
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)
Mitochondrial NAD⁺-dependent bifunctional enzyme that catalyzes two sequential reactions of the mitochondrial one-carbon folate cycle: (1) oxidation of 5,10-methylene-THF to 5,10-methenyl-THF (methylenetetrahydrofolate dehydrogenase activity, EC 1.5.1.15); (2) hydrolysis of 5,10-methenyl-THF to 10-formyl-THF (cyclohydrolase activity, EC 3.5.4.9). These reactions generate 10-formyl-THF, the folate cofactor required by GART and ATIC for de novo purine synthesis, and feed back 5,10-methylene-THF to TYMS for thymidylate synthesis. MTHFD2 is the rate-limiting enzyme of the mitochondrial one-carbon cycle and is broadly overexpressed in cancer relative to normal adult tissues (Nilsson et al. Nat Commun 2014; TCGA pan-cancer atlas), making it a validated metabolic oncology target. In SDH-deficient cells, the mechanistic case for MTHFD2 dependency arises from two convergent routes: (1) TCA truncation depletes the OAA/aspartate pool, limiting aspartate availability for pyrimidine synthesis (CAD); (2) accumulated succinate directly inhibits ATCase (the CAD complex), the first committed enzyme of de novo pyrimidine synthesis — established by Hart et al. (2025, PMID 42082831). The combined nucleotide stress activates the Integrated Stress Response (ISR) via GCN2 or HRI kinases (eIF2α phosphorylation → ATF4 selective translation), and ATF4 transcriptionally upregulates MTHFD2 as a compensatory one-carbon adaptation. Inhibiting MTHFD2 collapses this compensatory pathway and simultaneously depletes both purine and thymidylate branches, compounding the nucleotide depletion already imposed by SDH loss. Correction (2026-10-07): the former LY3410738 pairing was incorrect. LY3410738 is a mutant IDH1/IDH2 inhibitor (PMID 41026608; NCT04521686), not an MTHFD2/MTHFD1L inhibitor. No replacement drug was verified. The SDH-specific dependency proposed above remains an unvalidated hypothesis.
UniProt: P13995
Tumor Type Applicability
Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.
Coming in Phase 3
For research exploration only — not medical advice. Consult your doctor before acting on any information.
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.