Author(s): Mikaela Burtch, Reuben Dass, Celeste Litchfield, Jamison Cartwright
Mentor(s): James D. Moody, Matt Peterson
Institution BYU
Understanding protein structure is essential for deciphering protein function and utilizing this information to design drug candidates with high specificity. We employed X-ray crystallography to determine the structure of target proteins because it gives structural data at the atomic level. This accuracy of detail is critical to design small-molecule drug inhibitors that can effectively modulate protein activity. VPS34 is a lipid kinase that functions in signaling pathways to facilitate cell proliferation, differentiation, and metabolism. The dysregulation of VPS34 is frequently associated with cancer development. As of now, there are no inhibitors that have been approved by the FDA, in part due to insufficient specificity of binding which could lead to adverse health effects. In collaboration with the Matt A. Peterson lab, we synthesized a small molecule drug candidate RD-I-53 which specifically inhibits two kinases, JAK1 and VPS34, as determined by SAR activity. This is a notable feat as most kinase inhibitors are promiscuous. We obtained high resolution X-Ray diffraction data from diffracting VPS34 crystals and used this to solve the structure. Worthy of note is that we got crystals of VPS34 in less than 24 hours, and these crystals were then soaked with the drug candidate. We have been able to solve the structure of RD-I-53 bound to VPS34 and this will help us to further optimize the drug candidate and its derivatives until we optimize the candidate. Through this research, we will contribute to the ongoing efforts in precision medicine and the development of targeted therapeutic interventions.