Pol II-H Inhibitors

Chemical inhibitors of RNA polymerase II (Pol II-H) encompass a diverse range of compounds that target various aspects of the enzyme's function during the transcription process. α-Amanitin is one such inhibitor that exerts its effects by binding to the bridge helix within RNA polymerase II, a crucial component involved in the nucleotide addition cycle. This binding event hinders the translocation of RNA polymerase II along the DNA template, thus preventing the elongation phase of transcription. Similarly, DRB impairs the function of Pol II-H by targeting the C-terminal domain (CTD), precluding the necessary phosphorylation events required for transcription initiation and elongation. Triptolide takes a different approach by covalently binding to the XPB subunit of the transcription factor complex TFIIH, inhibiting the ATPase activity and consequently the initiation of transcription. Flavopiridol operates by inhibiting cyclin-dependent kinases (CDKs), which are integral to the phosphorylation of Pol II CTD, a modification essential for transcription progression.

Additional compounds that disrupt Pol II-H function include cordycepin, which integrates into the nascent RNA strand and induces premature termination by mimicking a nucleotide yet lacking the necessary hydroxyl groups for chain elongation. ICRF-193 obstructs the activity of topoisomerase II, an enzyme that modulates DNA supercoiling, a requirement for Pol II-H to effectively transcribe DNA. Actinomycin D, on the other hand, intercalates into DNA and stymies the progression of Pol II-H by physically blocking the transcription complex movement along the DNA strand. BAY 11-7082 abrogates the activation of NF-κB, a transcription factor that regulates genes processed by Pol II-H, thus indirectly affecting Pol II-H's function. Cantharidin impedes the activity of Pol II-H by inhibiting protein phosphatases 1 and 2A, altering the phosphorylation state of the CTD. Meayamycin is an inhibitors of Pol II-H; it binds to the transcription complex, preventing the release of the RNA transcript during elongation. Each of these chemicals utilizes a distinct mechanism to inhibit the transcriptional activity of Pol II-H.