Research Update from Dr. DasGupta at Cincinnati Children’s.

We have two aims in this project. In aim 1, we proposed to validate the mechanisms of action of Cpd14 in DIPG, and in Aim 2, we proposed to determine PK/PD and therapeutic efficacy of Cpd14 in our orthotopic mouse model of DIPG. Cpd14 continued to present solubility issues in vitro. Results of Cpd14 in the other line were inconsistent with the results we got using the first line, likely due to solubility problems. Therefore, we have temporarily stalled using Cpd14 as a therapeutic agent. However, the project took an exciting new turn. Cpd14 is an inhibitor of the enzyme ATIC. We discovered that antifolate inhibitors of ATIC synergize with inhibitors of one carbon metabolism and with diets reduced in folic acid. We are testing new drug combinations targeting ATIC and the folate pathway in vitro and in vivo.   For Aim 2, initial PK studies of Cpd14 have been completed which showed that Cpd14 penetrates the blood brain barrier. Because of the inconsistency in Cpd14 results, we are also collaborating with Dr. Ali Tavassoli in the UK to develop Cpd14 analogs using medicinal chemistry.