Identification of small-molecule inhibitors of human MUS81-EME1/2 by FRET-based high-throughput screening

Fragment-Based Discovery of Novel MUS81 Inhibitors

“… 9 , 11 − 13 There is thus interest in MUS81 as a potential cancer drug target, yet few small molecule inhibitors of this endonuclease have been reported. 14 Here, we report the fragment-based discovery of novel small molecule inhibitors of MUS81-EME1. Hit optimization resulted in compounds with sub-μM biochemical activity and favorable physicochemical and in vitro ADMET properties.…”

“…Following detailed inspection of these structures, two potential avenues for further improvement in the activity of the pyrimidinone series were evident: (1) the sterically unhindered (i.e., open) position of the phenyl group suggested significant scope for substitution of all positions of the ring, and ( 2) it appeared that interactions with the chelated Mg 2+ ions were key to ligand binding, suggesting further optimization of the Mg 2+ -binding (pyrimidinone) group to be potentially beneficial. To explore the phenyl ring of 5 further, we synthesized compounds with phenyl groups attached to the ortho (13), meta (14), and para (15) positions, with the ortho-substituted biphenyl further modified by the addition of a cyanomethyl group at the para position of the terminal phenyl group (16). While none of these modifications resulted in significantly increased affinity or biochemical activity, all were well-tolerated, giving single-digit μM K d and IC 50 values.…”

“…MUS81 is a structure-selective endonuclease that, when in complex with EME1, cleaves various branched DNA structures (such as Holliday Junctions) arising from natural physiological processes including homologous recombination and genetic recombination. − As homologous recombination is one of the major pathways by which cells repair DNA damage, MUS81 contributes to the maintenance of genome stability. As such, there is evidence in support of its function as a tumor suppressor. − Paradoxically, however, several recent studies have now implicated MUS81 activity in playing a role in the progression of several cancers, such as serous ovarian cancer and leukemia. , Additionally, inhibition of MUS81 activity has been shown to sensitize certain ovarian cancers to chemotherapeutic agents such as cisplatin, as well as to poly-ADP ribose polymerase inhibitors. ,− There is thus interest in MUS81 as a potential cancer drug target, yet few small molecule inhibitors of this endonuclease have been reported . Here, we report the fragment-based discovery of novel small molecule inhibitors of MUS81-EME1.…”