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CCS1477
Inobrodib
CBP/p300 bromodomain inhibitor
Evidence Score
27
CCS1477 (inobrodib; CellCentric/Ono Pharmaceutical) is an oral, selective small-molecule inhibitor of the CBP (CREBBP) and p300 (EP300) bromodomains. It competitively binds the acetyl-lysine-recognition pocket of the p300/CBP bromodomain, displacing the co-activator complex from acetylated histones and transcription factor C-TAD domains. The SDH-specific rationale flows directly from two established features of SDH-deficient biology: **1 — HIF-driven CBP/p300 co-activator dependency (universal across SDH tumors):** SDH loss → succinate accumulation → PHD2/PHD3 inhibition → VHL cannot target HIF-α for degradation → constitutive HIF-1α/2α stabilization. Arany et al. (PNAS 1996, PMID 8917528) established that HIF-1α transcriptional activation requires direct physical recruitment of CBP/p300 via the HIF C-terminal transactivation domain (C-TAD, residues 813–826). Without CBP/p300 bromodomain engagement, HIF-α cannot assemble a functional transcriptional activation complex at HREs. In SDH-deficient pseudohypoxic tumors, the HIF-α C-TAD is constitutively available — creating a chronic, SDH-loss-driven dependency on CBP/p300 co-activator recruitment for HIF target gene transcription (VEGF, GLUT1, CXCR4, PD-L1, BIRC5, IGF2, CAIX). Blocking the p300/CBP bromodomain with CCS1477 prevents C-TAD docking and collapses this HIF-driven transcriptional program. **2 — Super-enhancer maintenance at ectopic loci (SDH-deficient GIST):** Merriam et al. (Nat Med 2026, PMID 42191879) demonstrated that succinate-driven CIMP disrupts CTCF insulator elements flanking the FGF3/FGF4 locus in SDH-deficient GIST, creating high-occupancy super-enhancers characterized by dense H3K27ac marks. H3K27ac is deposited by the p300/CBP HAT domain. CBP/p300 bromodomain inhibition (CCS1477) prevents co-activator re-recruitment to these super-enhancers and is expected to collapse the FGF3/FGF4 super-enhancer program — the same program that rogaratinib (FGFR1 inhibitor) targets pharmacologically downstream. **Mechanistic distinction from existing engine entries:** - EZH2/tazemetostat (H3K27me3 WRITER, PRC2 complex; Mechanism 2): opposite histone mark, different chromatin state, different drug class. - BRD4/birabresib (H3K27ac READER, BET bromodomain; Mechanism 2): p300/CBP is the H3K27ac WRITER; inhibiting writing vs. reading are mechanistically orthogonal, use different drugs, and have non-overlapping target classes. - Belzutifan (HIF-2α direct inhibitor; Mechanism 1): targets HIF protein directly at the HIF-2α PAS-B pocket; CCS1477 targets the HIF co-activator complex, one step downstream in the transcriptional activation chain. **Clinical anchor:** CCS1477 (inobrodib) is in Phase 1b/2 clinical development (NCT04068597; CellCentric/Ono Pharmaceutical) in patients with metastatic castration-resistant prostate cancer and haematological malignancies including diffuse large B-cell lymphoma and multiple myeloma. The trial establishes human pharmacokinetics, target engagement, and an initial tolerability profile for the CBP/p300 bromodomain inhibitor class. **Limitations and evidence level:** No published preclinical data in SDH-deficient cell lines or xenograft models for CCS1477 or any CBP/p300 inhibitor. The mechanistic rationale rests on (1) the HIF-CBP/p300 C-TAD interaction (PMID 8917528), (2) the super-enhancer mechanism in SDH-deficient GIST (PMID 42191879), and (3) CCS1477 clinical-stage pharmacology in NCT04068597. Evidence_score 27 (theoretical) reflects a strong mechanistic basis in established SDH-deficient biology but no direct experimental validation in SDH-deficient models. Priority experiment: CBP/p300 inhibition in isogenic SDHA/B-null GIST or PPGL cell lines, using HIF target gene expression (VEGF, FGF3/FGF4) and H3K27ac ChIP-seq at HIF-driven super-enhancers as pharmacodynamic readouts.
Succinate inhibits TET family DNA demethylases and Jumonji-domain histone demethylases, causing global DNA and histone hypermethylation. This silences tumor suppressors and blocks differentiation.
Upstream event:
Succinate inhibits TET1/2/3 and KDM histone demethylases
Downstream effects:
HIF-1α and HIF-2α require CBP (CREBBP) and p300 (EP300) as obligate transcriptional co-activators. In SDH-deficient pseudohypoxic tumors, constitutively stabilized HIF-α subunits recruit CBP/p300 via the HIF C-TAD domain (Arany et al. PNAS 1996, PMID 8917528). p300/CBP then write H3K27ac marks at HIF target gene promoters and at ectopic super-enhancers — as demonstrated at the FGF3/FGF4 locus in SDH-deficient GIST (Merriam et al. Nat Med 2026, PMID 42191879). Blocking the p300/CBP bromodomain prevents co-activator recruitment to HIF-α C-TAD and collapses the SDH-loss-driven HIF transcriptome, including VEGF, CXCR4, PD-L1, BIRC5, and IGF2.
Upstream event:
SDH loss → succinate → PHD inhibition → HIF-1α/2α stabilization → HIF C-TAD domain recruits CBP/p300 bromodomain → p300/CBP HAT domain writes H3K27ac at HIF target promoters and super-enhancers
Downstream effects:
EP300
Histone acetyltransferase p300
p300 (encoded by EP300; UniProt Q09472) is a multidomain transcriptional co-activator and histone acetyltransferase (HAT). Its bromodomain binds acetylated lysine residues on histones and transcription factors; its KIX domain docks transactivation domains including the HIF-1α/2α C-TAD; its HAT domain transfers the acetyl group from acetyl-CoA onto histone H3K18 and H3K27, creating H3K27ac — the canonical active enhancer mark. The CBP paralogue (CREBBP; encoded by CREBBP/CBP) shares >60% sequence identity with p300 and is functionally redundant in the HIF co-activation context; both are grouped under the 'CBP/p300' druggable node. Relevance to SDH-deficient tumors: HIF-1α/2α require CBP/p300 as obligate co-activators to activate transcription at hypoxia-response elements (HREs). Arany et al. (PNAS 1996, PMID 8917528) established the direct physical interaction between the HIF-1α C-TAD (residues 813–826) and the CH1/cysteine-histidine-rich domain of CBP/p300. In SDH-deficient pseudohypoxic tumors, constitutive PHD inhibition by accumulated succinate locks HIF-1α/2α in their active conformations, creating chronic CBP/p300 co-activator dependency for HIF target gene transcription. Merriam et al. (Nat Med 2026, PMID 42191879) demonstrated in SDH-deficient GIST that succinate-driven CIMP disrupts CTCF insulator elements flanking the FGF3/FGF4 locus, creating ectopic super-enhancers. Super-enhancers are defined by their high H3K27ac density — directly produced by p300/CBP HAT activity at these loci. CBP/p300 therefore writes the histone acetylation code that maintains the GIST super-enhancer program. This makes p300 not merely a HIF co-activator but an active chromatin-remodeling enzyme at ectopic super-enhancers specific to SDH-deficient tumors. Druggable node: CCS1477 (inobrodib; CellCentric/Ono Pharmaceutical) is a selective p300/CBP bromodomain inhibitor that competitively displaces acetylated-lysine binding and prevents CBP/p300 co-activator recruitment to HIF-α C-TAD. Bromodomain inhibition is mechanistically distinct from HAT catalytic domain inhibition (A-485) and from BRD4/BET bromodomain inhibitors (targeting the H3K27ac reader, not writer). CCS1477 is in Phase 1/2 clinical development (NCT04068597; Phase 1b/2 in haematological malignancies and prostate cancer) with tolerability data established.
UniProt: Q09472
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.