The proposed research is envisioned to yield new small-molecule inhibitors of human MUS81 endonuclease. MUS81 plays critical role in resolution of late replication and recombination intermediates essential for proper segregation of chromosomes during mitosis. Its absence leads to accumulation of anaphase bridges, chromosomal breaks and fusions. Recent literature indicates that MUS81 represents a very promising target for pharmacological intervention, especially in the area of new anticancer therapies. It should be noted that until 2014, no crystal structure of human MUS81 was known. This, together with the fact that no small-molecule inhibitors of MUS81 have been reported yet, presents an excellent starting point for academic high-risk/high-gain project. This project represents unique interdisciplinary approach for proper medicinal chemistry optimization of our proprietary hit (compound 1B) together with its extensive in vitro and in vivo characterization. Furthermore, we will identify synthetic lethal partners for MUS81 deficiency with primary focus on clinically relevant genes. This together should lead to advanced leads that will be suitable for further preclinical (and possibly clinical) progression.

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