Targeting the chromatin-reader function of LEDGF/p75 for the treatment of Mixed-Lineage-Leukemia (TReaT-MLL)

Targeting the epigenome is gaining momentum in today’s drug discovery. Aberrant transcription due to dysregulation of epigenetic marks is one of the drivers for malignant transformation in many tumors. Mixed lineage leukemia (MLL)-rearranged acute leukemia (MLL-r) represents a genetically distinct subset of leukemia with poor prognosis (15-40 % event-free survival at 48 months). MLL r leukemia specifically originates from rearrangements in the MLL gene, mostly resulting in the formation of malignant fusion proteins or partial tandem duplications. Due to the interaction with the epigenetic reader LEDGF/p75 overexpression of MLL controlled Hox genes leads to uncontrolled growth of leukemic blasts. Here we propose to develop novel inhibitors of the LEDGF/p75-chromatin interaction that prevent leukemic transformation. To this end, a consortium will be formed at KUL bringing together disease and medicinal chemistry as well as state-of-the-art structural biology. These collective efforts will drive hit-to-lead optimization and ultimately the development of first-in-class drugs.

Keywords:mixed lineage leukemia, chromatin, epigenetics, drug discovery, LEDGF/p75-PWWP

Disciplines:Microbiology, Systems biology, Laboratory medicine, Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering