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Prexasertib
LY2606368
CHK1/CHK2 kinase inhibitor
Evidence Score
28
Prexasertib (LY2606368; Eli Lilly) is a potent, selective, ATP-competitive inhibitor of CHK1 (IC50 ~1 nM) with secondary CHK2 inhibition (IC50 ~8 nM). It is not FDA-approved and is under Phase 2 clinical evaluation in HR-deficient solid tumors. In SDH-deficient tumors, the mechanistic rationale flows directly from the established BRCAness phenotype. Sulkowski et al. (Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005) demonstrated that SDH loss causes succinate accumulation → inhibition of α-KG-dependent KDM4A and KDM4B histone demethylases → H3K9me3 persistence at double-strand break (DSB) sites → impaired TIP60 acetyltransferase and ATM kinase recruitment → defective HR repair (BRCAness). BRCAness-positive cells accumulate stalled replication forks that cannot be resolved by HR and become acutely dependent on the ATR→CHK1 replication stress checkpoint for survival. CHK1 performs three roles that are essential in BRCAness-positive cells: (1) inactivates CDC25A to suppress CDK2 and halt S-phase progression at stalled forks; (2) inactivates CDC25C to prevent premature CDK1 activation and mitotic entry with under-replicated DNA; (3) limits new origin firing to prevent collision with stalled forks. Prexasertib-mediated CHK1 inhibition in BRCAness-positive SDH-deficient cells causes unscheduled origin firing, replication catastrophe, RPA exhaustion, and premature mitotic entry → mitotic catastrophe and selective cell death. HR-proficient SDH-intact cells tolerate CHK1 inhibition via redundant fork protection mechanisms, providing a therapeutic window. This mechanism is distinct from ceralasertib (ATR inhibitor, Mechanism 13 in this engine): ATR acts upstream of CHK1 but ceralasertib's selectivity for SDH-deficient cells has been specifically linked to the ATRX-null/ALT replication stress subset (NCT03187965). CHK1 inhibition by prexasertib targets the BRCAness downstream effector relevant to ALL HR-deficient SDH-deficient tumors regardless of ATRX status, broadening the potential responder population. Clinical anchor: Do et al. (Clin Cancer Res 2021, PMID 34131002) reported a Phase 1 combination trial of prexasertib + olaparib in BRCA-mutant HGSOC, demonstrating 4/18 confirmed PRs and pharmacodynamic evidence of CHK1 target engagement (phospho-CDC25C reduction, γ-H2AX induction), validating the CHK1→HR impairment mechanistic chain in a clinical BRCAness context. NCT02873975 (Phase 2; Dana-Farber/Lilly; completed) enrolled patients with advanced solid tumors harboring 'Replicative Stress or Homologous Recombination Repair Deficiency', the clinically defined population that would encompass SDH-deficient BRCAness tumors. Key limitation: No published data directly test prexasertib in SDH-deficient cell lines or xenograft models. The BRCAness mechanism is genomically established (Sulkowski PMID 30013182, 32494005) but CHK1 inhibitor selectivity in SDH-specific models requires direct experimental validation. Evidence_score 28 (theoretical) reflects a well-anchored mechanistic chain from SDH loss → BRCAness → CHK1 dependency, combined with clinical prexasertib experience in HR-deficient solid tumors, without SDH-specific experimental data.
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 epigenetic silencing of homologous recombination (HR) repair factors — the BRCAness phenotype (Sulkowski et al. Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005). HR-deficient cells accumulate stalled replication forks and become acutely dependent on the ATR→CHK1 checkpoint kinase axis to stabilize forks, coordinate origin firing, and prevent premature mitotic entry. CHK1 (CHEK1) inhibition in BRCAness-positive cells causes replication catastrophe and mitotic catastrophe — a mechanistic vulnerability distinct from ATR inhibition (Mechanism 13, which is further restricted to ATRX-null/ALT subsets) because CHK1 is the downstream effector relevant to all BRCAness-positive SDH-deficient tumors regardless of ATRX status.
Upstream event:
SDH loss → succinate → KDM4A/KDM4B inhibition (α-KG-dependent histone demethylases) → H3K9me3 persistence at double-strand break sites → impaired TIP60 acetyltransferase and ATM kinase recruitment → HR deficiency (BRCAness) → stalled replication forks → CHK1 checkpoint activation → tumor CHK1 dependency for fork stability and cell cycle coordination
Downstream effects:
CHEK1
Checkpoint kinase 1 (CHK1)
Serine/threonine kinase and primary effector of the ATR-mediated replication stress response. CHK1 is phosphorylated by ATR at Ser317/Ser345 in response to single-stranded DNA (ssDNA) coated by RPA, which accumulates at stalled replication forks. Activated CHK1 inactivates CDC25A (by phosphorylation → ubiquitin-mediated degradation) to suppress CDK2 activity and arrest S-phase progression, and inactivates CDC25C to prevent premature CDK1 activation and mitotic entry. CHK1 also stabilizes stalled replication forks by limiting new origin firing and promoting fork restart. In SDH-deficient tumors, the BRCAness phenotype (Sulkowski et al. Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005) — epigenetic HR deficiency driven by succinate-mediated KDM4A/KDM4B inhibition and H3K9me3 accumulation at DSB sites — generates constitutive replication stress from stalled forks that cannot be efficiently repaired by HR. This creates an acute CHK1 dependency: BRCAness-positive SDH-deficient cells must rely on CHK1 to tolerate ongoing replication stress, whereas HR-proficient SDH-intact cells have redundant fork protection mechanisms. Synthetic lethality rationale: CHK1 inhibition in BRCAness-positive cells causes (1) unscheduled origin firing (origin dormancy is CHK1-regulated), (2) replication catastrophe from collision of active forks with unresolved stalled forks, (3) ssDNA accumulation and RPA exhaustion, and (4) premature mitotic entry of cells with under-replicated DNA → mitotic catastrophe and cell death. This mechanism applies to all BRCAness-positive SDH-deficient tumors, distinct from ceralasertib (ATR inhibitor, Mechanism 13) which is further restricted to the ATRX-null/ALT subset. Prexasertib (LY2606368, Eli Lilly) is the clinical-stage CHK1/CHK2 inhibitor with Phase 2 data in HR-deficient solid tumors.
UniProt: O14757
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.