APA
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Roggia, M., Chianese, U., Amendola, G., Albanese, V., Vetrei, C., Ieranò, C., … Cosconati, S. (2026). Targeting the Tumor-Stroma Crosstalk: An AI-Based Virtual Screening Strategy for Dual MET/SMO Inhibitors in Pancreatic Cancer. BioRxiv.
Chicago/Turabian
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Roggia, Michele, U. Chianese, Giorgio Amendola, Valentina Albanese, Cinzia Vetrei, C. Ieranò, C. D’Alterio, et al. “Targeting the Tumor-Stroma Crosstalk: An AI-Based Virtual Screening Strategy for Dual MET/SMO Inhibitors in Pancreatic Cancer.” bioRxiv (2026).
MLA
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Roggia, Michele, et al. “Targeting the Tumor-Stroma Crosstalk: An AI-Based Virtual Screening Strategy for Dual MET/SMO Inhibitors in Pancreatic Cancer.” BioRxiv, 2026.
BibTeX Click to copy
@article{michele2026a,
title = {Targeting the Tumor-Stroma Crosstalk: An AI-Based Virtual Screening Strategy for Dual MET/SMO Inhibitors in Pancreatic Cancer},
year = {2026},
journal = {bioRxiv},
author = {Roggia, Michele and Chianese, U. and Amendola, Giorgio and Albanese, Valentina and Vetrei, Cinzia and Ieranò, C. and D’Alterio, C. and Maro, S. Di and Ciardiello, F. and Morgillo, F. and Scala, S. and Altucci, L. and Preti, D. and Schulte, Gunnar and Benedetti, R. and Kozielewicz, P. and Cosconati, Sandro}
}
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense desmoplastic tumor microenvironment (TME) that limits drug penetration and promotes immune evasion. Effective treatment, therefore, requires simultaneous modulation of multiple signaling pathways. Here, we describe a directed polypharmacological strategy to identify dual modulators of c-MET and Smoothened (SMO), aiming to disrupt the protective stroma through SMO inhibition while directly suppressing tumor cell survival via c-MET targeting. An AI-guided virtual screening workflow combining the machine-learning platform PyRMD, trained on known c-MET and SMO ligands, with structure-based molecular docking was applied to a library of over 9 million compounds. This approach led to the identification of compound 21, an aminopyrimidine-benzamide-phenoxyquinoline derivative, as a dual c-MET/SMO inhibitor. Biochemical and cellular studies demonstrated that compound 21 selectively binds the SMO orthosteric site (pKi = 5.60), inhibits agonist-induced GLI (Glioma-associated oncogene) signaling (pIC50 = 5.50), and potently suppresses c-MET kinase activity (pIC50 = 6.94). Western blot analyses further revealed that compound 21 promotes ubiquitin–proteasome-mediated degradation of c-MET, eliminating receptor availability and limiting compensatory resistance signaling. In 3D heterotypic models comprising MIAPaCa2 pancreatic cancer cells and CAF154-hTERT fibroblasts, dual inhibition of SMO-mediated stromal support and c-MET-driven tumor progression resulted in greater cytotoxicity than the combination of the selective inhibitors Sonidegib and PHA-665752. Overall, compound 21 overcomes stromal-mediated resistance, enhances tumor cell death, and validates dual SMO/c-MET targeting as a promising single-agent therapeutic strategy for PDAC. One Sentence Summary An AI-identified dual SMO/c-MET inhibitor overcomes stromal resistance and degrades c-MET to suppress pancreatic cancer.