ETD

• ADAM17 inhibitors
• drug resistance
• dual inhibitors
• KRASG12C inhibitors
• KRASG12C mutation
• non-small cell lung cancer (NSCLC)

Lung cancer is the most commonly diagnosed cancer worldwide (12.4% of new cases) and the leading cause of cancer-related deaths (18.7%). It is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for about 85% of cases. One of the main genetic alterations in NSCLC involves the Kirsten-rat-sarcoma (KRAS) protein and, particularly, the G12C mutation, which accounts for around 40% of all KRAS-mutant cases. KRAS is a GTPase that regulates key cellular functions, and oncogenic mutations lock it in an active state, promoting uncontrolled cell growth. KRASG12C inhibitors such as Sotorasib and Adagrasib have been approved for NSCLC treatment, but their effectiveness is limited by resistance mechanisms. One such mechanism involves the upregulation of receptor tyrosine kinases (RTKs), often activated by the metalloprotease ADAM17, which is overexpressed in NSCLC and indirectly activated by mutant KRAS. The co-inhibition of ADAM17 and KRASG12C could represent a promising polypharmacological strategy, which may be able to overcome resistance to KRASG12C inhibitors in NSCLC. New dual inhibitors were identified through virtual screening based on the pharmacophores of both targets, followed by ligand- and structure-based analyses. The designed compounds feature an acrylamide moiety targeting the KRAS switch-II pocket, a sulfonamide group engaging the S1’ pocket of ADAM17 and a carboxylate group as a zinc-binding group essential for ADAM17 inhibition. These compounds will undergo in vitro testing against recombinant human ADAM17 and KRAS (wild-type and G12C mutant) at UniMORE.