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Fall 2022 challenge: phase 2 contenstant

Developing Selective VRK1 Inhibitors to Treat High-grade Gliomas

Jonathan So, Dana-Farber Cancer Institute, Cambridge, United States

We now have candidate analogues of our 4 small molecule hits found in our initial screen. A few challenges needed to be overcome. One was trying to choose the pose for the initial docking that we would then use to optimize the molecule. We ended up picking the pose with highest predicted affinity. Molecular dynamics simulations done with a collaborator on a example small molecule bound to VRK1 confirmed the relative accuracy of the docking.
After 3 months, Jonathan has achieved the following milestones:
  1. We took our 4 candidate small molecules and generated one analogue based on rational design and another using Inspirator mode to grow the molecule. Docking mode was then used to compare affinity of analogues for VRK1 vs. VRK2. We aimed to target VRK1 while sparing VRK2 kinase activity.
  2. We encountered some difficulties obtaining the analogues. We have now partnered with the Gray lab based out of Stanford to assist in synthesis as well as a chemical synthesis CRO. We hope to have a pilot set of analogues synthesized in the next few months.
  3. Waiting for analogues to be synthesized before sending to CRO for kinase assay testing.