One of the major complications of cancer is metastasis of a local tumor into other parts of the body. Small molecules that can prevent this process are therefore highly sought after due to their ability to keep a tumor in its local environment. Matrix metalloproteases (MMPs) have emerged as vital proteins in the digestion of connective tissue and the metastasis of tumors. Virtual Screening of the haemopexin domain of MMP9 has yielded the discovery of a highly selective inhibitor of MMP9-mediated cellular migration. Compound 1A emerged as a hit compound and a congeneric series of compounds based on 1A have been synthesized and modeled providing a structural basis for the enhanced activity in vivo of the molecular analogs of 1A such as 3C and 4D. Addition of two methylene units between the ring moieties of 1A enhances hydrogen bonding and predicted binding energy at the dimerization interface between MMP9 and cell signaling proteins, reducing cellular migration in vivo. Thus, structure-based drug design continued from the most potent compounds via Autodock Vina. Design began from the most potent compounds 3C and 4A based on readily synthesizable analogues. The resulting docking yielded several compounds with over 1.4 kcal/mol more favorable binding score such as Compound 6A. Other interesting trends emerged such as the poor predicted affinity for ortho and meta substituents on the benzimidazole/aniline moieties. The results provide a guiding rationale for discovery of small molecules with even better in vivo activity as anti-metastasis agents.

Design, synthesis, and SAR of matrix metalloprotease 9 inhibitors as anti-metastasis agents

2019 Spring National Meeting

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