Structure-based design of inhibitors targeting the chromatin-reading function of LEDGF/p75 to treat acute mixed-lineage leukemia

Mixed-lineage leukemia rearranged (MLL-r) is an acute leukemia mostly affecting children and associated with poor survival. The disease is caused by rearrangements in the MLL gene resulting in malignant fusion proteins. LEDGF/p75 serves as an epigenetic reader and tethers transcription complexes containing MLL to chromatin via its PWWP domain. Recent studies demonstrated that this process is essential for the onset of MLL-r leukemia, yet it is dispensable for hematopoiesis. Consequently, preventing the LEDGF/p75-chromatin interaction should displace the MLL complex from chromatin, downregulate MLL expression and reverse the malignant transformation. Here we propose to design and validate a novel class of small-molecule inhibitors that specifically bind to the nucleosome-recognizing site of LEDGF/p75. First, we will perform a direct crystallographic screening using already obtained PWWP domain crystals and a broad library of drug-like fragments. This recently developed approach is recognized as being efficient and robust. The obtained fragment hits will be grown into potential lead compounds through iterative cycles of in silico design, custom synthesis and biophysical in vitro testing to optimize their affinity and activity. The leads will be further evaluated in cell-based functional assays and eventually using animal models. Our final goal is to create first-in-class lead compounds for acute MLL-r leukemia.