Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Targeted therapy has been one of the most promising treatment options for cancer during the past decade. Discoveries of potent and selective small molecule inhibitors are critical to new and promising targeted therapy. Pleckstrin Homology (PH) domain proteins are one of the biggest protein families in the human proteome. However, no drugs have been achieved to the late development stages, let alone getting to the market. Thus, a deeper understanding of this protein family is required and there is an urgent need to develop novel small molecule compounds targeting these proteins.
Studies of PH domains began around two decades ago and a lot of efforts have been focused on their structures and functions. However, not much is known about their role in cancers, except a few proteins such as AKT. In order to delineate the roles of PH domain proteins in cancers, we performed a comprehensive analysis of 313 PH domain proteins using 13 types of most common cancers in TCGA. From this analysis, we identified the most frequently upregulated and mutated PH domain proteins. Interestingly, we found Tiam1, a guanine nucleotide exchange factor (GEF) specific for Rac1 activation, was overexpressed in several cancers, particularly neuroendocrine prostate cancer.
Targeting PH domain proteins remains to be a significant challenge for multiple reasons. First, the binding pockets of most PH domain proteins are unknown due to lacking of PH-PIPs complex crystal structures. Second, these binding pockets are positively charged, which makes it really difficult to design small molecule inhibitors targeting these sites. In order to address these issues, we performed structural sequence alignment of available PH domain structures to identify conserved residues. Also, ensemble docking was performed in order to address the flexibility of the proteins. Through these efforts, we identified two scaffolds as Tiam1 small molecule inhibitors. These inhibitors showed binding affinity to the PH domain using surface plasmon resonance (SPR) assay and inhibition of Rac1 activation in prostate cancer cells. Also, these compounds inhibited prostate cancer cell proliferation and migration in vitro.
Pleckstrin homology domain; PH domain; Prostate cancer; Drug discovery; Precision Medicine; Targeted Therapy