Exploring the therapeutic potential of a novel series of imidazothiadiazoles targeting focal adhesion kinase (FAK) for pancreatic cancer treatment: Synthesis, mechanistic Insights and promising antitumor and safety profile

Abstract

Focal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumors, such as pancreatic ductal adenocarcinoma (PDAC). Herein, we report a new series of twenty imidazo[2,1-b][1,3,4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound 10l exhibited effective antiproliferative activity against immortalized (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC50 values in the low micromolar range (1.04-3.44 {micro}M), associated with a significant reduction in cell-migration and spheroid shrinkage in vitro. High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumor cell invasion and apoptosis induction. The low selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumor growth and safety. In conclusion, compound 10l displayed antitumor activity and safety in both in vitro and in vivo models, emerging as a highly promising lead for the development of FAK inhibitors in PDAC.