TPH-3

TPH-3 is a novel small molecule inhibitor designed to target the phosphoinositide lipid-binding Pleckstrin Homology (PH) domain of TIAM1 (T-lymphoma invasion and metastasis-inducing protein-1). TIAM1 is a guanine nucleotide exchange factor (GEF) that activates Rac1 and is often overexpressed in various cancers, including breast, colon, and prostate cancers, where it correlates with increased metastatic potential and poor prognosis. By binding to the PH domain with high affinity, TPH-3 displaces PtdIns-3,4,5-P3 and inhibits the activation of Rac1. In preclinical studies, TPH-3 has demonstrated the ability to reduce active Rac1 levels in PC-3 prostate cancer cells and inhibit cell proliferation, migration, and invasion. It was identified through in silico screening and validated via surface plasmon resonance (SPR) and in vitro assays.