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Daporinad (FK866)

APO866

NAMPT inhibitor (NAD⁺ biosynthesis inhibitor)

Evidence Score

48

preclinical
Mechanism of Action

Highly potent, non-competitive inhibitor of NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the NAD⁺ salvage pathway. SDH-deficient cells accumulate ROS from dysfunctional Complex II, driving chronic PARP1 activation for DNA single-strand break repair; PARP1 is the dominant intracellular NAD⁺ consumer under genotoxic stress. Concurrently, the truncated TCA cycle makes cells dependent on cytoplasmic NAD⁺ regeneration via the malate-aspartate shuttle and glycolysis. Daporinad depletes intracellular NAD⁺, simultaneously collapsing PARP-mediated repair capacity and bioenergetic reserves. Birsoy et al. (Cell 2015, PMID: 26232224) demonstrated that ETC-deficient cells have an absolute NAD⁺ dependency for aspartate synthesis and proliferation. Phase 1 safety data established (Hovstadius et al., Clin Cancer Res 2002, PMID: 12231528); Phase 2 trials for hematologic malignancies (NCT00432107). Key limitation: dose-limiting thrombocytopenia requires careful scheduling.

Pathway Connections
Oxidative Stress / ROS

Complex II dysfunction causes electron leak in the electron transport chain, increasing reactive oxygen species (ROS). This drives DNA damage but also creates a therapeutic vulnerability.

Upstream event:

Impaired electron flow through Complex II → electron leak

Downstream effects:

Increased ROS productionOxidative DNA damageGenomic instabilityPARP activation for DNA repairTherapeutic vulnerability to further ROS stress
NAD⁺ Metabolism / NAMPT Axis

SDH loss impairs Complex II of the electron transport chain, causing NADH accumulation and increased mitochondrial ROS. Sustained ROS drives DNA damage that chronically activates PARP1, consuming NAD⁺. Cells compensate by upregulating the NAMPT-mediated NAD⁺ salvage pathway, creating a targetable dependency.

Upstream event:

Complex II dysfunction → NADH/NAD⁺ imbalance + ROS-driven DNA damage → PARP1 hyperactivation

Downstream effects:

Chronic NAD⁺ depletionPARP-mediated parthanatos vulnerabilityGlycolytic NAD⁺ regeneration dependencyNAMPT upregulation as adaptive responseSelective lethality to NAD⁺ biosynthesis inhibition
Molecular Targets

NAMPT

Nicotinamide phosphoribosyltransferase

metabolic

Rate-limiting enzyme in the NAD⁺ salvage pathway; converts nicotinamide to NMN, the immediate NAD⁺ precursor. SDH-deficient cells with elevated PARP1 activity and impaired ETC-mediated NAD⁺ regeneration upregulate NAMPT as an adaptive survival response, creating a dependency exploitable by NAMPT inhibitors such as daporinad (FK866).

UniProt: P43490

Quick Facts
Not FDA Approved
ChEMBL IDCHEMBL267023
PubChem CID5459942
Evidence

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.

AI Analysis

Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.