One of the ongoing projects at SGC-UNC is the development of chemical probes for understudied kinases (e.g. MST1-4, TAOK1-3, DCAMKL1, MAP3K2 and MAP3K3). A chemical probe is defined as a small molecule that selectively and potently modulates a protein’s function. Generating chemical probes for understudied kinases is important so we can further understand the biology of these kinases. To achieve this goal, we are preparing a set of pyrimido-diazepine compounds based around a previously reported scaffold that is potent against several of these understudied kinases that was originally published by Nathanael Gray. In order to understand the SAR (structure activity relationship) we aim to generate several analogs and screen them in biochemical assays to validate their activity. At the same time, linkable versions of some of these compounds will be synthesized that will enable the development of a split-luciferase binding assays for these kinases. These assays will be developed in collaboration with Luceome Biotechnologies and will help them expand their KinaseSeeker™ Assay panel.
Figure 1. Linkable fused pyrimidine synthesis