Cell reports · 2026
AI-driven discovery and validation of a GIPC1 PDZ domain inhibitor for pancreatic ductal adenocarcinoma.
СтатьяНазвание и аннотация: Перевод в очереди
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Rachamala Hari Krishnareddy, Rao Nakka Naga Malleswara, Angom Ramcharan Singh, Varanasi Sai Manasa, Wei Fang, Kulkarni Tanmay, Dutta Shamit Kumar, Wang Enfeng, Kulkarni Nagaraj M, Geoffrey A S Ben, Hegde Shraddha Prabhakar, Perumal Saravanan, Gurram Kishan, Gharibi Hassan, Gaetani Massimiliano, Mukherjee Sourav Pr, Babiker Hani, Pal Krishnendu, Mukhopadhyay Debabrata
Аннотация
Pancreatic ductal adenocarcinoma (PDAC) remains highly aggressive, with a five-year survival rate under 13.3%, due to late diagnosis, rapid progression, and therapeutic resistance, highlighting the need for advanced treatments. GAIP-interacting protein C terminus 1 (GIPC1), a scaffolding protein overexpressed in PDAC, drives tumor growth and chemoresistance but has remained "undruggable" due to its PDZ domain. Using advanced computational modeling, machine learning, and predictive analytics, we identified a selective and specific small molecule inhibitor of GIPC1 (GIPCi) targeting its PDZ domain. Binding of GIPCi with GIPC1 protein itself was confirmed via hydrogen-deuterium exchange mass spectrometry (HDX-MS). Preclinical studies showed that GIPCi alone or in combination with gemcitabine (GEM) significantly suppressed tumor growth and improved survival in PDAC models by blocking key pro-tumorigenic pathways. These findings demonstrate the power of AI-driven drug discovery and rigorous validation in unlocking advanced therapeutic targets for treatment-resistant cancers like PDAC.