The Hippo signaling pathway holds a key role in cancer metastasis through the induction of epithelial-mesenchymal transition (EMT) and thus stands as an opportunity for novel anticancer drug targets. We identified a small molecule (C19) that demonstrates inhibitory activity towards the Hippo pathway, as well as the Wnt and TGF-β pathways. C19 suppressed cancer cell migration, proliferation, and antitumor activity in a mouse tumor model through activation of the Hippo kinases Mst/Lats and the metabolic regulator AMPK. Our small molecule inhibitor contains a core 1,2,5-thiadiazole ring, which was optimized with respect to both the aromatic and the aliphatic side chain, to improve cellular introduction, cytoplasmic stability, binding pocket interactions, and IC<sub>50</sub> values. Through computational protein-ligand modeling, biological signaling analysis, and bioisostere optimization, we have synthesized and characterized several derivatives of C19 that also hold potential as small molecule inhibitors of these signaling pathways for novel cancer therapeutics.

Optimization of thiadiazole small molecule inhibitor of the hippo signaling pathway to reduce pro-EMT cancerous cell growth

249th National Meeting (2015)

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