Developing Small-Molecule Inhibitors of GATA2

Acute myeloid leukaemia (AML) is an aggressive cancer occurring in blood and bone marrow, where blood cells are produced. Due to DNA mutations, the bone marrow rapidly produces many malfunctioning white-blood cells, which, over time, start to crowd out the healthy cells, making the bone marrow stop functioning properly and the body more susceptible to infections.

Current AML treatments are non-specific and toxic, because they also kill normal white-blood cells, and are often ineffective. In some cases, AML appears back again. AML is initiated and sustained by a group of cells, Leukaemia Stem Cells (LSCs), which are very resistant to current treatments and cause AML to appear again. We found that blocking the activity of GATA2, a protein overexpressed in LSCs, causes LSCs death.

We also discovered a new molecule able to block GATA2, which exclusively kills AML cells. Starting from these results, this project will use computer-based techniques to design novel molecules to block GATA2. These molecules will be constructed in a chemistry laboratory, and then tested against AML cells grown in the lab. Following this, we aim to develop the first specific GATA2 inhibitors, which will subsequently be optimised into novel treatments to target LSCs in therapy-resistant AML.