Based on the results reported here, we anticipate that pharmacologically mimicking the L828F structural/dynamic state with a small molecule could result in synthetic lethality in cancer cells when combined with DNA damage inducing agents, such as topoisomerase I inhibitors, and a checkpoint kinase (CHK1/2) inhibitor, as MRN would be improperly regulated and downstream ATM signaling would be disrupted. The gene discussed is CHEK1; the disease is cancer.