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Olaparib

Lynparza

PARP inhibitor (PARP1/2)

Evidence Score

58

preclinical
Mechanism of Action

Selective PARP1/2 inhibitor that traps PARP at unrepaired single-strand breaks, converting them to cytotoxic double-strand breaks at replication forks. The mechanistic rationale in SDH-deficient tumors is a confirmed 'BRCAness' phenotype: succinate competitively inhibits the α-KG-dependent histone demethylases KDM4A and KDM4B, causing aberrant H3K9me3 hypermethylation at DNA double-strand break sites. This blocks TIP60 acetyltransferase and ATM kinase recruitment, impairing DNA end-resection and homologous recombination (HR) — despite wild-type BRCA1/2 (Sulkowski et al., Nature 2020, PMID: 32494005). Sulkowski et al. (Nat Genet 2018, PMID: 30013182) directly demonstrated HR deficiency and olaparib hypersensitivity in patient-derived FH-deficient and SDH-deficient hereditary paraganglioma/PPGL cells, establishing PARP inhibition as a mechanistically grounded synthetic lethality — not merely a ROS-amplification strategy. Multiple clinical trials are exploring PARP inhibitors in non-BRCA hereditary cancer syndromes based on this rationale. Key limitation: prospective clinical data in SDH-deficient patients specifically are not yet available; biomarker-selected trials (RAD51 foci, HRD genomic scar score) are needed to confirm the HR-deficient phenotype in SDH-deficient tumors in vivo.

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
Succinate-Driven Homologous Recombination Deficiency

Succinate accumulation competitively inhibits the α-KG-dependent histone demethylases KDM4A and KDM4B (JMJD2A/B), which normally erase repressive H3K9me3 marks at sites of DNA double-strand breaks. When KDM4B is inhibited, H3K9me3 hypermethylation persists at break sites, blocking recruitment of TIP60 acetyltransferase and ATM kinase — both required for DNA end-resection and initiation of homology-directed repair (HDR/HR). The result is a 'BRCAness' phenotype: SDH-deficient tumor cells have impaired HR capacity despite wild-type BRCA1/2. Sulkowski et al. (Nat Genet 2018, PMID: 30013182) directly demonstrated HR deficiency and olaparib hypersensitivity in cells and tumors from SDH-deficient hereditary paraganglioma/PPGL patients; Sulkowski et al. (Nature 2020, PMID: 32494005) dissected the KDM4B/H3K9me3 chromatin mechanism.

Upstream event:

SDH loss → succinate accumulation → competitive inhibition of KDM4A/KDM4B (α-KG-dependent H3K9me3 demethylases) → H3K9me3 persistence at DNA double-strand break sites → impaired TIP60/ATM recruitment → defective DNA end-resection → HR deficiency

Downstream effects:

H3K9me3 hypermethylation at DNA double-strand break sitesImpaired TIP60 acetyltransferase and ATM kinase recruitmentDefective homologous recombination (BRCAness phenotype in BRCA1/2-wild-type cells)PARP inhibitor synthetic lethality (trapping unrepaired single-strand breaks in HR-deficient background)Selective sensitivity to olaparib and other PARP inhibitors in SDH-deficient versus SDH-intact cells
Molecular Targets

PARP1

Poly(ADP-ribose) polymerase 1

synthetic_lethal

DNA repair enzyme activated by ROS-induced damage. PARP inhibition in ROS-elevated cells may cause synthetic lethality.

UniProt: P09874

KDM4B

Lysine demethylase 4B (JMJD2B)

direct

Primary α-KG-dependent H3K9me3 demethylase at DNA break sites. KDM4B is the demethylase whose oncometabolite-mediated inhibition was identified as the mechanistic basis for HR deficiency in succinate-accumulating (SDH-deficient) and fumarate-accumulating (FH-deficient) tumors. Sulkowski et al. (Nature 2020, PMID: 32494005) showed that 2-HG, succinate, and fumarate all inhibit KDM4B, causing H3K9me3-masked DNA breaks that cannot recruit the HR machinery; restoration of KDM4B activity rescued HR competence. Together with KDM4A, KDM4B constitutes the α-KG-dependent chromatin checkpoint for DNA end-resection.

UniProt: O94953

Quick Facts
FDA Approved

Approved Indications

  • BRCA-mutated ovarian cancer
  • BRCA-mutated breast cancer
  • BRCA-mutated pancreatic cancer
  • HRD-positive prostate cancer
ChEMBL IDCHEMBL521686
PubChem CID23725625
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.