Protein kinases are a class of enzymes that transfer phosphate groups from ATP to specified substrates, resulting in structural and functional modifications to substrate activity. Cell division, signaling, and metabolism are all affected by the phosphorylation of proteins via post-translational modification by protein kinases. Within the past few decades, protein kinase research has emerged at the forefront of chemical biology as one of the primary areas of interest in drug development. An estimated total of 500 protein kinases exist in the human kinome. However, only a small fraction of these have been subjected to studies regarding biological function and therapeutic targeting.<br/>A common practice in determining the function and mechanism of a protein kinase is the synthesis and utilization of small-molecule chemical probes. These inhibitors are targeted towards a specified protein and subsequently elucidate pathways in both healthy and diseased cells. From this verification, the probe can serve as a precursor to a therapeutic drug in combating the disease in question. Our project focuses on the inhibition of kinase STK16, an understudied serine-threonine kinase.  STK16 is also known to phosphorylate DRG1 (developmentally regulated GTP-binding protein 1), but the biological consequences of these interactions remain unknown. A recent paper reported the discovery of a STK16 inhibitor that caused binucleation and arrested cell growth in some cancer lines. However, this reported inhibitor was not screened for activity against other families of enzymes and was also found to be a strong inhibitor of mTOR, a kinase known to regulate cell growth. In contrast, another paper reported that kinase-dead STK16 mutants of the HT1080 cell line did not display binucleation, but rather decreased expression of VEGF leading to lower angiogenesis activity. These conflicting results make it clear that a high-quality chemical probe is needed to unravel the biological function of this ubiquitously expressed kinase.  To that end, we report our progress synthesizing rationally designed STK16 inhibitors featuring an aminooxazole core.

Synthesis of 2-aminooxazole inhibitors targeting kinase STK16

ACS Spring 2022

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