FANCB Inhibitors

Chemical inhibitors of FANCB function by interfering with the cellular processes that it facilitates, primarily the repair of DNA damage. Mitomycin C, Cisplatin, and Diepoxybutane all contribute to the formation of DNA crosslinks which can be particularly burdensome for the DNA repair machinery in which FANCB plays a critical role. These crosslinking agents directly challenge the Fanconi Anemia (FA) pathway through the introduction of lesions that FANCB is responsible for addressing. With an overwhelming presence of such crosslinks, FANCB is functionally inhibited as the repair mechanism it supports is overloaded. Similarly, Etoposide and Camptothecin exacerbate the amount of DNA breaks within the cell. Etoposide's stabilization of the DNA-topoisomerase II complex and Camptothecin's inhibition of topoisomerase I both lead to an increase in DNA breaks. FANCB, being a part of the complex network that repairs such damage, is functionally inhibited when the quantity of DNA damage exceeds the repair capacity of the FA pathway. Amsacrine and Teniposide, both topoisomerase II inhibitors, introduce a high frequency of DNA breaks which can saturate the FA pathway and in turn inhibit FANCB. The impaired function of FANCB is a result of the insurmountable DNA damage that it is tasked to repair. Bortezomib, while not directly interacting with DNA, disrupts proteostasis, affecting the cellular environment that is integral for FANCB's optimal function. By perturbing the balance of protein turnover, it can indirectly inhibit the FANCB protein's role in DNA repair. PARP inhibitors such as Veliparib, Olaparib, Talazoparib, and Rucaparib amplify DNA damage by preventing the repair of single-strand breaks. This escalation in DNA damage results in more complex double-strand breaks that challenge the FA pathway's repair capabilities. The functional inhibition of FANCB arises from the increased demand for repair that is imposed by these PARP inhibitors, thus overwhelming the FA pathway's finite resources and repair machinery.