Effective pharmaceutical treatments capable of truly curing myelodysplastic syndrome (MDS) are urgently needed by the MDS community. Patients with therapy-related MDS, as well as other types of cancer, often have elevated levels of a protein called PPM1D, which is a critical regulator of how cells respond to DNA damage. A recent breakthrough revealed that blocking PPM1D greatly increased the sensitivity of cancer cells to commonly used chemotherapies. This discovery highlights PPM1D as an important drug target to enhance current treatments for leukemias, as well as to treat specific cases of t-MDS or cancers with high levels of PPM1D. Motivated by these findings, we are exploring a new way to control PPM1D activity. Our preliminary data support a hypothesis that oxygen-sensitive parts of the PPM1D protein regulate its ability to respond to DNA damage and will provide an entirely new way to therapeutically target PPM1D. We will investigate this new regulatory pathway and specifically target its oxygen-sensing abilities using a modern class of chemical inhibitors. To ensure the success of this project, we have assembled an interdisciplinary team with complementary expertise in protein structure/function, mass spectrometry, and MDS. The project would generate innovative tools for the EvansMDS research community, laying the groundwork for a new pathway to drug discovery.