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Ym155 (Sepantronium Bromide)
YM155, Sepantronium
Survivin (BIRC5) transcription inhibitor / IAP inhibitor
Evidence Score
31
Ym155 (sepantronium bromide) suppresses transcription of BIRC5 (survivin) by displacing the transcription factor Sp1 from the CDE/CHR elements in the BIRC5 promoter, reducing survivin mRNA and protein levels. The mechanistic rationale for selectivity in SDH-deficient tumors rests on two converging lines. First, SDH loss drives pseudohypoxic HIF-1α stabilization (via succinate-mediated PHD inhibition), and the BIRC5 promoter contains canonical HRE elements through which HIF-1α transcriptionally upregulates survivin above the already-elevated baseline found in most cancers. Second, SDH-deficient cells accumulate unrepaired DNA double-strand breaks via the KDM4B/H3K9me3 BRCAness mechanism (Mechanism 14). In wild-type cells, such DNA damage triggers caspase-mediated apoptosis; in SDH-deficient cells, HIF-1α-driven survivin elevation suppresses caspase-3/7 and forms a ternary anti-apoptotic complex with XIAP and caspase-9, allowing cells to tolerate an otherwise lethal DNA damage load. Ym155 targets both functions simultaneously: depleting survivin removes both the apoptosis block and the CPC/spindle checkpoint support on which genomically unstable SDH-deficient cells depend for mitotic fidelity. Direct SDH-deficient evidence: PMID 41711310 (Endocr Relat Cancer 2026) demonstrated that SDH-deficient cancer cells show significantly increased susceptibility to Ym155-induced DNA damage versus SDH-intact controls — a selectivity that is consistent with the dual BRCAness/Survivin-dependency model. Clinical data: Phase 2 data in relapsed/refractory non-Hodgkin lymphoma (NCT00390117) showed partial responses with survivin suppression confirmed pharmacodynamically; dose-limiting toxicity includes renal impairment at higher doses, manageable with adequate hydration. Key limitations: (1) no dedicated SDH-deficient tumor trial exists; (2) the specific degree of HIF-1α-driven BIRC5 upregulation in SDH-deficient GIST versus PPGL models has not been measured; (3) Ym155 showed limited single-agent activity in Phase 2 solid tumor studies (NCT00437957), suggesting combination strategies or patient selection by BIRC5 expression/HIF-1α level may be required.
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:
Pseudohypoxic HIF-1α stabilization — a universal consequence of SDH loss — transcriptionally activates BIRC5 (survivin), an inhibitor of apoptosis (IAP) family protein. The survivin promoter contains canonical hypoxia-response elements (HREs) directly bound by HIF-1α. Elevated survivin in SDH-deficient cells enables two pro-tumor functions: (1) apoptosis evasion by inhibiting caspase-3/7 and forming a ternary anti-apoptotic complex with XIAP and caspase-9, protecting cells from executing the apoptosis that would normally follow accumulated DNA damage; and (2) mitotic survival as a core subunit of the Chromosomal Passenger Complex (CPC), which governs spindle assembly checkpoint and chromosomal segregation in genomically unstable cells. SDH-deficient cells accumulate DNA damage via BRCAness (Mechanism 14) but evade apoptosis through elevated Survivin — creating a synthetic lethal dependency on BIRC5 that can be exploited by Survivin inhibitors. Direct evidence: PMID 41711310 demonstrated selective susceptibility of SDH-deficient cancer cells to the Survivin inhibitor Ym155 (Endocr Relat Cancer 2026).
Upstream event:
SDH loss → succinate accumulation → PHD inhibition → HIF-1α stabilization → HRE-driven BIRC5/Survivin transcriptional upregulation
Downstream effects:
BIRC5
Baculoviral IAP repeat-containing protein 5 (Survivin)
IAP (inhibitor of apoptosis) family protein encoded by BIRC5. Survivin inhibits caspase-3/7-mediated apoptotic execution and serves as a core subunit of the Chromosomal Passenger Complex (CPC) governing mitotic fidelity. Its promoter contains canonical hypoxia-response elements (HREs) directly activated by HIF-1α, making BIRC5 a transcriptional target of the pseudohypoxic program that is constitutively active in all SDH-deficient tumors. SDH-deficient cells with elevated Survivin depend on BIRC5 to evade apoptosis despite accumulated DNA damage from BRCAness; BIRC5 knockdown or inhibition with Ym155 shows selective susceptibility in SDH-deficient cancer cell lines (PMID 41711310).
UniProt: O15392
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.