polymerase-II

RNA polymerase II-IN-1 (compound 19iv), an amatoxin, selectively inhibits RNA polymerase II (Pol II) with an IC50 of 36.66 nM and exhibits heightened cytotoxicity towards cancer cells while reducing toxicity in normal cells compared to α-Amanitin [1].

RNA polymerase II-IN-2 (compound 20iii), a potent inhibitor of RNA polymerase II (Pol II) with a K i value of 9.5 nM, exhibits cytotoxicity against cancer cells, demonstrating toxicity levels 2 and 5 times higher than α-amanitin in CHO and HEK293 cells, respectively [1].

AOH1996 is an orally active ligand for the replicasome component PCNA (proliferating cell nuclear antigen), targeting the transcription-replication conflict (TRC). It interferes with the interaction of PCNA with its binding proteins, leading to DNA replication stress and apoptosis. AOH1996 causes proteasome-dependent rpb1 degradation and lethal DNA damage by stabilizing the interaction between PCNA and RNA polymerase II, and acts synergistically with DNA damaging agents to inhibit tumor cell growth.

(S)-Enitociclib (VIP152) is a selective CDK9 inhibitor that induces complete regression of MYC+ lymphomas by inhibiting RNA polymerase II-mediated transcription of anti-apoptotic and pro-survival proteins.

A09-003 is a novel cell cycle protein-dependent kinase-9 CDK-9 inhibitor.A09-003 inhibits the proliferation of a variety of leukemia cell lines and inhibits the increase of leukemia sequence-1 protein in myeloid cells.A09-003 also induces apoptosis, decreases RNA polymerase II activity, and decreases Mcl-1 expression.

CBL 0100 free base is an HIV-1 transcription inhibitor that blocks HIV-1 replication and reactivation in vitro and in ex vivo models. It targets the chromatin-associated transcription (FACT) complex, reducing the occupancy of RNA Polymerase II and FACT in the HIV-1 promoter region, and can be used as a latency-reversing agent (LRA) in cART therapy.

AZD-4573 is a selective and short-acting inhibitor of the serine threonine cyclin-dependent kinase 9, the catalytic subunit of the RNA polymerase II elongation factor positive transcription elongation factor b. It also has a potential antineoplastic activ

Mycophenolic acid-d3 (Mycophenolate-d3) is a derivative of Mycophenolic acid. Mycophenolic acid is a compound that reduces GTP level and impacts transcription elongation of RNA polymerase II (RNAP II), promotes proximal site use and reverses the effect of cordyceps on selective polyadenylation.

β-Amanitin, a cyclic peptide toxin found in the poisonous Amanita phalloides mushroom, inhibits eukaryotic RNA polymerase II and III, thereby disrupting protein synthesis.

Mal-C6-α-Amanitin, an ADC (antibody-drug conjugate) linker drug, incorporates the powerful antitumor agent α-Amanitin, an inhibitor of RNA polymerase II, through the Mal-C6 linker, showcasing potent antitumor activity.

CDK12/13-IN-3 (Compound 12b) is an orally active CDK inhibitor targeting CDK12 and CDK13, with IC50 values of 107.4 nM and 79.4 nM, respectively. This compound inhibits the phosphorylation of Ser2 on the CTD of RNA polymerase II, induces DNA damage, and downregulates the gene expression involved in the DNA damage response (DDR). CDK12/13-IN-3 exhibits antiproliferative effects against various cancer cells with nanomolar IC50 values. In mouse models, it demonstrates antitumor activity, favorable pharmacokinetic properties, and an oral bioavailability of 53.6%.

CDK12-IN-8 (Compound Cpd143) is an orally active, highly selective inhibitor of cyclin-dependent kinase 12 (CDK12). It blocks the phosphorylation of serine 2 in the C-terminal domain (CTD) of RNA polymerase II, thereby interfering with gene transcription elongation and DNA damage repair pathways. CDK12-IN-8 holds potential for research in cancers with high CDK12 expression, such as small cell lung cancer and triple-negative breast cancer.

YX0597 is a potent and selective CDK9 PROTAC degrader that reduces RNA polymerase II S2 phosphorylation and MCL1 expression in GA0518 and AGS cells. It effectively inhibits the growth of GEAC cells (including radioresistant tumors) and suppresses tumor proliferation, metastasis, and cancer stem cells.

5-formylcytosine (5FC) is a rare base found in mammalian DNA. It participates in active DNA demethylation, changes DNA double helix structure, and reduces the transcription rate and substrate specificity of RNA polymerase II.

TAF10 is one of many protein factors or coactivators associated with RNA polymerase II activity. One vial of this peptide may be used as a methyltransferase acceptor peptide for more than 200 reactions at 15 μM.

cDPCP is a platinum-containing DNA-crosslinking agent.1Unlike cisplatin or oxaliplatin , cDPCP forms monofunctional DNA adducts. It is transported into cells by organic cation transporter 1 (OCT1) and OCT2, inhibiting proliferation of MDCK cells expressing the human transporters with IC50values of 8.1 and 1.5 μM, respectively. cDPCP inhibits RNA polymerase II-mediated transcription in a reporter assay using HeLa cells. It increases survival in murine S180 sarcoma and P388 leukemia models when administered at doses of 40 and 80 mg/kg, respectively.2 1.Lovejoy, K.S., Todd, R.C., Zhang, S., et al.cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospectsProc. Natl. Acad. Sci. USA105(26)8902-9807(2008) 2.Hollis, L.S., Amundsen, A.R., and Stern, E.W.Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor)Cl]+J. Med. Chem.32128-136(1989)

γ-Amanitin, an ADC (antibody-drug conjugate) cytotoxin isolated from mushrooms, inhibits RNA polymerase II, disrupting mRNA synthesis. It exhibits effects akin to those of α-Amanitin and β-Amanitin.

ε-Amanitin is a cyclic peptide obtained from various mushroom species. It exhibits a strong affinity for RNA polymerase II and effectively inhibits its activity.

Thio-ITP, also known as 6-Thioinosine 5'-triphosphate, is a competitive inhibitor of RNA polymerase activity. It exhibits a strong apparent affinity towards the polymerases, with Ki values of 40.9 μM for RNA polymerase I and 38.0 μM for RNA polymerase II.

POL1-IN-1 (Compound 3A) can effectively inhibit the transcription of RNA polymerase I in the A375 malignant melanoma cell line but has no effect on polymerase II.

CDK-IN-9 (compound 24) is a potent inhibitor of CDK and acts on CDK2/E (IC50: 4 nM). It functions as a molecular gel that induces interaction between CDK12 and DDB1, and can dephosphorylate retinoblastoma protein and RNA polymerase II, thereby inducing apoptosis.

CDK7-IN-2 is a potent inhibitor of CDK7, which plays a role in transcription initiation via phosphorylation of the Rbpl subunit of RNA polymerase II (RNAPII). CDK7 is linked to the temporal control of the cell cycle and transcriptional activity, and has research potential for aggressive and difficult-to-treat cancers.

BSJ-01-175 is a selective and potent covalent inhibitor of CDK12 13. BSJ-01-175 is significantly selective for cancer cells, exhibits potent inhibition of phosphorylated RNA polymerase II, and significantly downregulates CDK12 target genes.

Pidnarulex HCl is the salt form of CX-5461, a first-in-class non-genotoxic small molecule targeted inhibitor of RNA polymerase I (Pol I) that activates the p53 pathway without causing DNA damage. CX-5461 selectively inhibits rRNA synthesis by Pol I in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II) and does not inhibit DNA replication or protein synthesis. Inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and liberate p53 to orchestrate apoptosis in cancer cells. CX-5461 demonstrates a favorable preclinical profile, potently and selectively kills cancer cells, demonstrates robust in vivo efficacy in multiple models, and has demonstrated oral bioavailability in multiple species.