NBS1 Inhibitors

Chemical inhibitors of NBS1 can disrupt its function in various DNA repair pathways by targeting key proteins that interact with or modify NBS1. Mirin, for example, inhibits the MRN complex, which is integral to the DNA damage response, by specifically targeting the Mre11-Rad50 interaction, thereby impairing the ability of NBS1 to facilitate DNA repair. NU7026, by inhibiting DNA-PK, can obstruct the non-homologous end joining (NHEJ) pathway, where NBS1 is essential for recruiting DNA-PK to DNA double-strand breaks, thus functionally inhibiting NBS1's role in DNA repair. Similarly, KU-55933 and CGK733 inhibit ATM kinase, which is responsible for phosphorylating NBS1 as part of the DNA damage response. Without this phosphorylation, NBS1's role in signaling and repair of DNA damage is reduced.

In addition to ATM kinase inhibitors, chemicals that target ATR kinase also play a crucial role in inhibiting NBS1. VE-821, AZ20, and ETP-46464 are ATR inhibitors that prevent the phosphorylation of NBS1 by ATR, a critical step for the activation of the DNA damage response involving NBS1. Furthermore, PF-477736 and LY2603618 are Chk1 inhibitors, and since Chk1 can phosphorylate NBS1, their inhibition can impede NBS1's function in DNA damage checkpoints and repair. Wortmannin serves as a broad PI3K inhibitor that affects the PIKK family members, including ATM and ATR, preventing the phosphorylation and proper function of NBS1 in the DNA damage response. CP-466722 is another ATM inhibitor, preventing ATM's phosphorylation of NBS1, which is necessary for NBS1 to function effectively in DNA double-strand break repair signaling. Each of these inhibitors, by targeting specific enzymes that act upon NBS1, can compromise NBS1's ability to participate in the cellular response to DNA damage.