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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

Tumor Type Applicability

All SDH tumors
Not FDA Approved
ChEMBL IDCHEMBL267023
PubChem CID5459942
Clinical Trials
NCT00432107
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.