SLX1A/B_SLX1 Inhibitors

Camptothecin and Etoposide are topoisomerase inhibitors that introduce breaks into DNA. These breaks become the lesions that the SLX1A/B_SLX1 complex is recruited to repair. The increased frequency of such lesions can saturate the repair capacity of the cell, leading to an indirect inhibition of the complex as it becomes overwhelmed with substrate. Likewise, Mitomycin C and Cisplatin, by forming DNA crosslinks and adducts, respectively, also impose a heavy burden on the DNA repair system. The complex's function is indirectly hindered as it struggles to keep up with the demand for repair, potentially disrupting the normal cell cycle and leading to cell death if the damage is irreparable. Other inhibitors, such as Hydroxyurea, reduce the availability of deoxynucleotide triphosphates (dNTPs), the building blocks of DNA, by inhibiting ribonucleotide reductase. This limitation can indirectly affect the SLX1A/B_SLX1 complex as DNA synthesis during repair is compromised. Similarly, Aphidicolin, by stalling DNA polymerase activity, leads to replication stress and the accumulation of stalled replication forks, which are substrates for the SLX1A/B_SLX1 complex. The consequent backlog can exhaust the complex's repair capacity.

Inhibitors that target key signaling molecules in the DNA damage response, such as ATR inhibitor VE-821 and KU-55933, which inhibits ATM kinase, disrupt the finely tuned regulatory mechanisms that coordinate DNA repair. These disruptions can indirectly affect the SLX1A/B_SLX1 complex by altering its recruitment or activity in response to damage. NU7441, a DNA-PKcs inhibitor, and Mirin, an MRE11 inhibitor, affect pathways that intersect with those requiring the SLX1A/B_SLX1 complex, thereby modulating its activity through changes in pathway dynamics. Lastly, B02, a RAD51 inhibitor, impedes one of the key proteins involved in homologous recombination, a process in which the SLX1A/B_SLX1 complex is also involved. This inhibition can lead to an increased load of DNA repair work for the complex, again leading to an indirect form of inhibition as the complex is faced with an overwhelming number of substrates.