Design and development of dual KRas-G12C/ADAM17 inhibitors for the treatment of resistant Non-Small Cell Lung Cancer

Non-Small Cell Lung Cancer (NSCLC) is one of the most aggressive and prevalent tumors worldwide, unfortunately with limited therapeutic options available. According to recent evidence, most NSCLC cases harbor mutations in Kirsten rat sarcoma virus (KRas), particularly the G12C variant, which drive tumor progression and metastasis. Patients bearing mutant KRas commonly develop resistance to targeted therapies, mainly due to insurgence of secondary oncogenic mutations and overactivation of signaling pathways, many of which are regulated by A Disintegrin and Metalloproteinase 17 (ADAM17). Given the close functional interplay between mutant KRas and ADAM17, their simultaneous inhibition is expected to provide more effective therapeutic responses against drug-resistant NSCLC bearing mutant KRas. Recent studies suggest that polypharmacology strategies targeting multiple cancer pathways with a single compound can offer enhanced efficacy, reduced toxicity, and superior pharmacokinetic profiles compared to monotherapies or conventional combination regimens. On these grounds, this project aims to develop the first, drug-like dual inhibitors of ADAM17 and KRas-G12C, as an innovative and more effective therapeutic strategy to treat drug-resistant forms of NSCLC. In particular, we aim at demonstrating that: (i) co-targeting of ADAM17 and KRas-G12C with a single compound can help to prevent or overcome drug resistance to KRas-G12C inhibitors, and; (ii) this strategy is feasible and can be translated to effective treatments to NSCLC in preclinical settings. To this aim, we will perform the design of KRas-G12C/ADAM17 dual inhibitors, by means of chemoinformatics, artificial intelligence and structure-based approaches. Selected candidates will be synthesized and evaluated through extesive enzyme- and cell-based assays, including testing against advanced NSCLC organoid models. Lastly, the therapeutic efficacy of the most promising dual inhibitors will be assessed using xenograft tumor models. Overall, this project is expected to provide the first KRas-G12C/ADAM17 dual inhibitors with favorable drug-like profiles, capable of overcoming drug resistance in NSCLC, identifying also novel polypharmacological strategies readily translatable into viable treatments against resistant cancers.