POLR2D Inhibitors

Chemical inhibitors of RNA polymerase II (Pol II) subunit POLR2D employ various mechanisms to impede the transcription process. α-Amanitin, for example, directly targets Pol II by binding to it and preventing the enzyme from transcribing DNA into messenger RNA (mRNA). This binding is highly specific and results in the strong inhibition of the enzyme's activity.. The action of α-Amanitin showcases a profound effect on the POLR2D subunit's function, as POLR2D is integral to the Pol II complex. Triptolide, on the other hand, interferes with the transcription machinery by covalently binding to the XPB subunit of the transcription factor IIH (TFIIH) complex, which is crucial for transcription initiation. This binding disrupts the assembly and stability of the initiation complex, thus inhibiting the transcriptional activity of Pol II.

Other compounds such as DRB, Actinomycin D, and Cordycepin demonstrate additional unique mechanisms of action. DRB acts by blocking the phosphorylation of the C-terminal domain (CTD) of the Pol II largest subunit, which is essential for the elongation of transcripts. This affects POLR2D by halting the progression of the polymerase along the DNA. Actinomycin D exerts its inhibitory effect by intercalating into DNA at the transcription initiation complex, thereby preventing the elongation phase of transcription by RNA polymerase II. Cordycepin, a nucleoside analog, terminates the mRNA chain elongation by incorporating into the growing RNA chain. This leads to a premature halt in the transcription process, indirectly affecting POLR2D's role. Lastly, Tagetitoxin binds to and stabilizes the transcription initiation complex, preventing the transition into the elongation phase, which is essential for POLR2D's activity within the transcription process. Each of these inhibitors, through distinct interactions with the POLR2D subunit or associated complexes, effectively impedes the overall process of transcription as conducted by RNA polymerase II.