Targeting Clinically Viable Protein-Protein Interactions via Rationally Designed Small Molecule Inhibitors

Malfunctions in the tightly regulated network of Protein-Protein Interactions (PPIs) are the basis for numerous malignancies such as cancer. Novel protein targets that are critical components of this network and key in preserving cellular homeostasis are important targets for discovery of new therapeutics. This thesis explores the components required for the engineering of small-molecule inhibitors to target key disease-driving PPIs. The first section focuses on designing inhibitors against the oncogenic, Signal Transducer and Activator of Transcription 3 (STAT3) protein. First, a pharmacopore model was developed to inspire the synthesis of suitably functionalized 2,6,9-hetero-tri-substituted purines. Numerous candidates from this library displayed cancer-cell specific potency and high affinity to the STAT3 protein. Despite promising activity in vitro, the analogs displayed poor cell permeability leading to the development of a second generation of prodrug and bioisosteres to address these drawbacks. In a separate study, we investigated the optimization of a previous lead STAT3 inhibitor for targeting STAT3 in Brain Tumor Stem Cells (BTSCs). Prodrug and bioisostere analogs were prepared of the key carboxylic acid, as well as salicylic acid mimetics and evaluated for STAT3 binding and cellular activity. A new lead, SH-04-54 (ACS Med Lett, 2013), was identified which exhibited Blood Brain Barrier (BBB) permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. The potent activity of this inhibitor led to its entry into preclinical trials as an anti-cancer agent. Finally, the last part of this thesis focuses on PTP1B, a member of the large PTP family of proteins found to be overactive in diabetes and neurodegenerative disorders. First, a screen of a library of compounds identified a number of potent salicylic acid based inhibitors with promising single digit µM activity. A second generation of disalicylic inhibitors were synthesized and new, more selective and potent inhibitors have been identified.Ph.D.2016-07-10 00:00:0