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ART558
POLQ inhibitor (DNA polymerase theta inhibitor)
Evidence Score
27
ART558 is a first-in-class, selective, orally bioavailable inhibitor of DNA polymerase theta (POLQ), the effector enzyme of Pol θ-mediated end-joining (TMEJ, also called microhomology-mediated end-joining / MMEJ) — the major backup DSB repair pathway in homologous recombination (HR)-deficient cells. The mechanistic rationale in SDH-deficient tumors is a second-order synthetic lethality built on the established BRCAness mechanism (Mechanism 14). SDH loss drives succinate accumulation, which competitively inhibits the α-KG-dependent histone demethylases KDM4A and KDM4B at DNA double-strand break (DSB) sites. H3K9me3 persistence at DSBs blocks TIP60 acetyltransferase and ATM kinase recruitment, impairing DNA end-resection and creating an HR-deficient state in all SDH-deficient cells — regardless of BRCA1/2 mutation status (Sulkowski et al., Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005). HR-deficient cells upregulate POLQ/TMEJ as a compensatory backup: Ceccaldi et al. (Nature 2015, PMID 25642963) demonstrated that POLQ expression is elevated in HR-deficient tumors, and that POLQ depletion is synthetically lethal with HR deficiency in ovarian cancer cell lines and xenografts, while having minimal effect on HR-proficient cells. ART558 blocks POLQ's polymerase activity, preventing TMEJ-mediated DSB resolution. When both HR and TMEJ are unavailable — as in SDH-deficient cells treated with ART558 — unrepaired DSBs accumulate and drive cell death. The POLQ/TMEJ direction is mechanistically distinct from and complementary to PARP inhibition in the same BRCAness context: PARP inhibitors (olaparib, niraparib) trap SSBs that collapse into DSBs during replication, which HR-deficient cells cannot resolve via HR; POLQ inhibition (ART558) blocks the backup TMEJ pathway that those same HR-deficient cells depend on to survive their accumulated DSB burden. Combining ART558 with PARP inhibitors may yield additive or synergistic lethality in SDH-deficient tumors by simultaneously generating unresolvable DSBs and blocking both remaining DSB repair routes. ART558 is being developed by Artios Pharma and is in Phase 1 clinical investigation in solid tumors harboring DNA-damage-response defects. Key limitation: no published data exist directly testing POLQ inhibition in SDH-deficient cell lines or xenografts; the mechanistic case rests on the Ceccaldi synthetic lethality framework in HR-deficient cancer (PMID 25642963) combined with the Sulkowski SDH-BRCAness papers (PMID 30013182, PMID 32494005). SDH-specific preclinical validation is the critical next step.
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:
SDH loss drives succinate accumulation, which competitively inhibits KDM4A/KDM4B (α-KG-dependent H3K9me3 demethylases) at DNA double-strand break sites. H3K9me3 persistence blocks TIP60/ATM recruitment and DNA end-resection, producing a global homologous recombination (HR) deficiency — the 'BRCAness' phenotype described by Sulkowski et al. (Nat Genet 2018; Nature 2020). HR-deficient cells cannot repair DSBs via the high-fidelity HR route and instead upregulate Pol θ-mediated end-joining (TMEJ, also called MMEJ), the backup DSB repair pathway executed by DNA polymerase theta (POLQ). TMEJ is error-prone (generating short deletions and microhomology footprints) but essential for survival when HR is unavailable. Ceccaldi et al. (Nature 2015, PMID 25642963) demonstrated that HR-deficient cancer cells are synthetically lethal with POLQ inhibition or depletion: when both HR and TMEJ are unavailable, unrepaired DSBs cause cell death. ART558, a first-in-class selective POLQ inhibitor (Artios Pharma), exploits this dependency and is in Phase 1 clinical development. The POLQ/TMEJ direction is mechanistically complementary to PARP inhibition in the same BRCAness context: PARP inhibitors trap SSBs that collapse into DSBs, which HR-deficient cells cannot resolve; POLQ inhibition blocks the backup TMEJ pathway those same cells depend on to survive accumulated DSBs.
Upstream event:
SDH loss → succinate accumulation → KDM4A/KDM4B inhibition → H3K9me3 persistence at DSBs → HR deficiency (BRCAness) → compensatory TMEJ/POLQ upregulation
Downstream effects:
POLQ
DNA polymerase theta
DNA polymerase theta (POLQ) is the effector enzyme of Pol θ-mediated end-joining (TMEJ, also called MMEJ), the major backup pathway for DNA double-strand break repair in homologous recombination (HR)-deficient cells. POLQ extends from short microhomology sequences exposed after resection, bridging and ligating the break ends in an error-prone manner. Ceccaldi et al. (Nature 2015, PMID 25642963) established the synthetic lethal relationship between HR deficiency and POLQ in ovarian cancer: POLQ expression is elevated in HR-deficient tumors, POLQ depletion selectively kills HR-deficient cells, and the combination of HR deficiency + POLQ loss is non-viable. In SDH-deficient tumors, succinate-mediated inhibition of KDM4A/KDM4B creates a universal (all-DSB, all-SDH-deficient-cell) HR deficiency (Sulkowski et al., Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005); this should drive compensatory POLQ/TMEJ upregulation, creating synthetic lethality with POLQ inhibitors. ART558 (Artios Pharma) is the first-in-class selective, oral POLQ inhibitor; it is in Phase 1 clinical development in solid tumors with DNA-damage-response defects.
UniProt: O75417
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.