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Denifanstat
TVB-2640
FASN inhibitor (fatty acid synthase inhibitor)
Evidence Score
35
Orally bioavailable, selective inhibitor of fatty acid synthase (FASN), targeting the β-ketoacyl reductase (KR) domain. The mechanistic rationale in SDH-deficient tumors rests on a directly demonstrated FASN-SDHB synthetic lethal interaction: Rodríguez-Flores et al. (Pharmacol Res 2026, PMID 41520938) showed that the FASN inhibitor G28UCM impairs both cytoplasmic FASN activity and mitochondrial fatty acid synthesis (mtFAS) selectively in SDHB-knockout cell lines versus WT controls, establishing class-level synthetic lethality. The metabolic logic is two-layered. First, SDH loss truncates the TCA cycle at the succinate → fumarate step, forcing cells to rely on reductive carboxylation of glutamine (reverse IDH1/2: glutamate → α-KG → isocitrate → citrate; then ACLY cleavage to acetyl-CoA) as their primary cytoplasmic acetyl-CoA and lipid precursor route. FASN is the terminal enzyme of this route, producing palmitate and longer fatty acids for membrane biogenesis and lipid-dependent signalling. Second, FASN products supply octanoyl-ACP to the mitochondrial fatty acid synthesis (mtFAS) pathway, which generates lipoic acid — an essential cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KG-DH). In SDH-deficient cells already impaired at Complex II, FASN inhibition therefore compounds mitochondrial insufficiency through two routes: withdrawing membrane lipids and blocking mtFAS-derived lipoylation of key enzyme complexes. Denifanstat (TVB-2640) is the most clinically advanced FASN inhibitor, with Phase 1 safety data established in multiple solid tumor types (NCT02980029) and Phase 2 activity signals in HER2+ breast cancer (FASN overexpression cohort) and malignant astrocytoma (NCT04341337). No dedicated SDH-deficient-specific trial exists; the class effect demonstrated with G28UCM (PMID 41520938) provides the SDH-specific mechanistic anchor; denifanstat's superior oral bioavailability and selectivity profile make it the preferred clinical candidate over the experimental G28UCM compound. Key limitation: the precise contribution of mtFAS impairment versus cytoplasmic de novo lipogenesis blockade to the SDHB-synthetic lethality remains to be dissected, and no in-vivo SDH-deficient xenograft data for FASN inhibition has been published.
With the TCA cycle disrupted at Complex II, SDH-deficient cells become addicted to glutamine for anaplerosis and lipid synthesis via reductive carboxylation.
Upstream event:
TCA cycle disruption at succinate → fumarate step
Downstream effects:
SDH loss truncates the TCA cycle at the succinate → fumarate step, forcing cells to generate lipid precursors via reductive carboxylation of glutamine: glutamate → α-KG → isocitrate → citrate (reverse TCA via IDH1/IDH2), which is exported to the cytoplasm and cleaved by ATP-citrate lyase (ACLY) to yield acetyl-CoA. Fatty acid synthase (FASN) then converts acetyl-CoA and malonyl-CoA into palmitate and longer-chain fatty acids required for membrane biogenesis, lipid signalling, and mitochondrial lipid supply. Independently, FASN products are required for mitochondrial fatty acid synthesis (mtFAS), which produces the lipoic acid moiety needed by key mitochondrial enzyme complexes. A FASN-SDHB synthetic interaction was directly demonstrated using the FASN inhibitor G28UCM in SDHB-knockout cell lines: G28UCM impaired FASN activity and mitochondrial fatty acid synthesis more profoundly in SDHB-deficient cells than in WT controls, establishing selective synthetic lethality (Rodríguez-Flores et al., Pharmacol Res 2026, PMID 41520938).
Upstream event:
SDH loss → TCA cycle truncation at Complex II → reductive glutamine carboxylation as primary citrate-generation route → ACLY-mediated cytoplasmic acetyl-CoA production → upregulated FASN-mediated de novo fatty acid synthesis; concurrent dependence on FASN products for mitochondrial lipid supply and mtFAS
Downstream effects:
FASN
Fatty acid synthase
Multifunctional cytoplasmic enzyme catalyzing de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA. In SDH-deficient cells, the truncated TCA cycle forces acetyl-CoA generation via reductive carboxylation of glutamine (reverse IDH1/2 reaction: α-KG → isocitrate → citrate; ACLY cleavage: citrate → acetyl-CoA), making FASN the terminal effector of a glutamine-dependent lipid supply route. FASN products also feed mitochondrial fatty acid synthesis (mtFAS), which produces the lipoic acid cofactor required by pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes; in cells already compromised at Complex II, additional impairment of mtFAS via FASN inhibition compounds mitochondrial dysfunction. A direct FASN-SDHB synthetic lethal interaction was demonstrated using G28UCM (a FASN KS-domain inhibitor) in SDHB-knockout cell lines: G28UCM impaired FASN activity and mitochondrial fatty acid synthesis more profoundly in SDHB-deficient cells than in WT controls (Rodríguez-Flores et al., Pharmacol Res 2026, PMID 41520938). Primary clinical candidate: denifanstat (TVB-2640).
UniProt: P49327
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.