Decreased cellular signaling in the insulin signaling pathway leads to type 2 diabetes; therefore, a way to get around this reduced sensitivity is to prolong the signal that does occur. If the intracellular phosphatase that regulates the duration of the insulin receptor signal, protein tyrosine phosphatase 1B (PTP1B), is inhibited, the signal will be prolonged and such an inhibitor could have therapeutic benefits for those who suffer from type 2 diabetes. Inhibitors of PTP1B that target the active site have problematic properties for pharmaceuticals, including both lack of specificity and bioavailability, but allosteric inhibitors may not suffer these problems. Additionally, it is important for inhibitors to be nonaggregating, as aggregating compounds are not specific for the protein of interest and behave inconsistently. To work towards the goal of finding a non-aggregating allosteric inhibitor of PTP1B, three classes of heterocyclic compounds that were deemed potential non-aggregating allosteric inhibitors through computational methods were synthesized. A concentration dependent <sup>1</sup>H-NMR assay was used to test the compounds for aggregation. Standard enzymatic assays were employed to determine the mode of inhibition of PTP1B and the IC<sub>50 </sub>of active compounds. Each of the compounds in the quinazoline class was deemed an aggregator, leading to inconsistent inhibition. The maleimide class and amino maleimide class were nonaggregating but did not inhibit PTP1B. Through the synthesis and analysis of potential allosteric inhibitors of PTP1B, progress was made towards finding an inhibitor with therapeutic benefits for type 2 diabetes patients.

Developing an allosteric inhibitor of PTP1B for therapeutic applications

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.