SBI-115

Overview

SBI-115 is a selective antagonist of the G-protein-coupled bile acid receptor GPBAR1 (TGR5). In cholangiocarcinoma (CHOL), TGR5 has a context-dependent role: hepatoprotective in early cholestasis (M2 macrophage polarization, NF-kB suppression) but pro-tumorigenic in advanced CCA, where it drives ERK1/2 phosphorylation via Src/EGFR transactivation and confers apoptosis resistance through PKA-mediated CD95 inactivation. SBI-115 targets the pro-tumorigenic arm.

Evidence in the corpus

• SBI-115 (TGR5/GPBAR1 antagonist) reduces pro-fibrotic and metastatic signaling in CCA preclinical models by blocking the Src/EGFR transactivation and PKA/CD95-mediated apoptosis resistance driven by TGR5 in advanced disease; the hepatoprotective (early cholestasis) vs pro-tumorigenic (advanced CCA) duality of TGR5 complicates agonist/antagonist selection PMID:25608663

Resistance mechanisms

• TGR5 functional duality across disease stages (hepatoprotective in early cholestasis, pro-tumorigenic in advanced CCA) lacks defined stage thresholds, complicating therapeutic window for SBI-115 PMID:25608663

Cancer types (linked)

• CHOL — cholangiocarcinoma

Sources

• PMID:25608663

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