TFIIIB Inhibitors

Chemical inhibitors of TFIIIB target various aspects of the transcription machinery and related cellular processes to achieve inhibition. Triptolide directly inhibits the activity of RNA polymerase II, which is crucial for the transcriptional activity of TFIIIB, leading to a reduction in its function. Similarly, α-Amanitin binds to and inhibits RNA polymerase II, resulting in a halt in transcription that TFIIIB is dependent on. DRB, known as 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole, acts by inhibiting the phosphorylation of RNA polymerase II, an essential post-translational modification required for transcription elongation, thereby hindering TFIIIB function. Actinomycin D intercalates into DNA, preventing the formation of the transcription complex that includes TFIIIB, while Camptothecin traps the DNA-topoisomerase I complex, thereby preventing the progression of transcription that involves TFIIIB. Flavopiridol inhibits CDK9, part of the positive transcription elongation factor b (P-TEFb), which in turn is necessary for the full functionality of TFIIIB.

Further inhibitory effects on TFIIIB are achieved through agents that target DNA topology and chromatin structure. ICRF-193 and ICRF-187 both bind to DNA topoisomerase II, an enzyme that modulates DNA's topological states, essential for transcription by RNA polymerase II and consequently for TFIIIB activity. Leptomycin B disrupts nuclear export by binding to exportin, leading to a decrease in the nuclear availability of certain transcription factors and potentially reducing TFIIIB activity due to insufficient transcription factor concentration. Cordycepin leads to premature termination of mRNA synthesis, which can result in the reduction of the transcriptional activity of TFIIIB. Trichostatin A inhibits histone deacetylases, causing changes in chromatin architecture that can lead to reduced transcriptional activity involving TFIIIB. Lastly, Oxaliplatin forms DNA adducts and interstrand crosslinks, impeding RNA polymerase II progression and thus inhibiting the transcriptional engagement of TFIIIB. Each of these chemicals exerts its inhibitory effect through distinct interactions with the transcriptional machinery or the DNA substrate, ultimately diminishing the functional capacity of TFIIIB.