A Candidate SmallMolecule Targeting Tachykinin Receptor1 Suppresses Substance P-Driven Extracellular Signal-RegulatedKinase Activation and Tumor Innervation in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive tumor-nerve interactions that contribute to tumor progression, therapeutic resistance, and neural remodeling. Substance P (SP) and its receptor tachykinin receptor 1 (TACR1) have been implicated in cancer-associated neurogenic signaling, but pharmacological strategies to intercept this axis in PDAC remain insufficiently explored. Here, we identified TACR1 as a candidate druggable receptor expressed in pancreatic cancer cells and used structure-guided virtual screening of a mini-scaffold compound library to prioritize small molecules with predicted TACR1-binding potential. Among the top-ranked compounds, C547 showed TACR1 target engagement in cellular thermal shift assays and preferentially suppressed SP-induced growth and proliferation in TACR1-high MIA PaCa-2 cells, with limited effects in TACR1-low PANC-1 cells. C547 also attenuated SP-induced migration, reversed SP-associated reduction in gemcitabine sensitivity, and reduced the expression of epithelial–mesenchymal transition- and neurotrophin-associated genes. Mechanistically, SP increased ERK phosphorylation, whereas C547 reduced SP-driven ERK activation. Importantly, TACR1 knockdown diminished the inhibitory effects of C547 on cell growth and migration, supporting TACR1-dependent pharmacological activity. In an orthotopic KPPC pancreatic cancer model, C547 reduced tumor burden and decreased PGP9.5-positive tumor innervation without overt gross toxicity. These findings nominate the SP–TACR1-ERK axis as a pharmacologically targetable neuro-oncogenic pathway in PDAC and support C547 as a candidate TACR1-targeting lead compound for further optimization.