Scaffold optimization trends in matrix metalloproteinase inhibitors for selective pancreatic cancer Therapy—A review

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its dense stromal barrier, aggressive invasion, and resistance to therapy. Matrix metalloproteinases (MMPs), zinc-dependent endopeptidases responsible for extracellular matrix remodeling, play a critical role in PDAC progression, metastasis, and tumor microenvironment modulation. Consequently, selective inhibition of MMP isoforms has emerged as a promising therapeutic strategy. Early hydroxamate-based MMP inhibitors demonstrated potent activity but failed clinically due to poor selectivity, zinc chelation-related toxicity, and limited pharmacokinetic profiles. Recent medicinal chemistry efforts have focused on scaffold modification to overcome these challenges, leading to the evolution of alternative zinc-binding groups (ZBGs) such as carboxylates, phosphonates, thiols, and sulfonamides. This review systematically summarizes scaffold optimization trends in MMP inhibitors, correlating structural features with enzyme selectivity and anticancer efficacy. Structure–activity relationship (SAR) studies highlight the role of aromatic and polar substituents in enhancing binding affinity and isoform discrimination. Additionally, computational modeling, pharmacophore mapping, and molecular docking analyses provide mechanistic insights into ligand-enzyme interactions within the catalytic Zn²⁺ site. The review also discusses crystallographic data and structure-based drug design approaches that guide next-generation MMP inhibitor development. Collectively, this work emphasizes medicinal chemistry strategies for designing potent, selective, and bioavailable MMP inhibitors, thereby advancing rational therapeutic approaches for targeted PDAC management.