RNA Polymerases Inhibitor

Myxopyronin B is an α-pyrone natural product derived from Myxococcus fulvus and acts as an inhibitor of the switch region of bacterial RNA polymerase (RNAP) (IC₅₀ = 24 μM). Myxopyronin B binds to the switch region of RNA polymerase, locking the polymerase clamp into a closed conformation and thereby inhibiting transcription initiation. Myxopyronin B exhibits antibacterial activity against Staphylococcus aureus and Clostridioides difficile, inhibits the early synthesis of toxins A and B, and reduces the abundance of proteins in the branched-chain amino acid fermentation pathway. Myxopyronin B is useful for research related to bacterial infections.

ZLMT-72 is an orally active dual CDK2 and CDK9 inhibitor with IC₅₀s of 0.741 nM and 1.03 nM, respectively. ZLMT-72 shows good selectivity in kinase profiling andcholinesterase inhibition activity. ZLMT-72 has strong antiproliferative effects in the colorectal cancer (CRC) cell line HCT116 (GI₅₀ < 0.1 nM). ZLMT-72 induces apoptosis by inhibiting thephosphorylation of retinoblastoma and RNA polymerase II, resulting in downregulation of antiapoptotic proteins (Mcl-1 and XIAP). ZLMT-72 can be used for the study of colorectal cancer (CRC).

PB2-IN-4 is a potent and orally effective PB2 inhibitor with an IC₅₀ of 82 nM. PB2-IN-4 inhibits viral RNA polymerase activity and gene expression by binding to the PB2 protein, and alleviates the host inflammatory response. PB2-IN-4 can be used for research on influenza A virus.

Dideoxy-amanitin (compound 2), an α-Amanitin (HY-19610) derivative, is a potent and selective RNA polymerase II allosteric inhibitor with an IC₅₀ value of 74.2 nM.

Fluoroneplanocin A-8N (Compound 3a) is an inhibitor targeting SAH hydrolase (IC₅₀ = 1.51 μM) and viral RNA polymerase. Fluoroneplanocin A-8N exhibits broad-spectrum anti-SARS-CoV-2 and dengue virus activity, with EC₅₀ values of 12.2 and 37.4 μM respectively. Fluoroneplanocin A-8N has no cytotoxicity. Fluoroneplanocin A-8N can be used for anti-positive-strand viruses.

DENV-IN-4 is a potent DENV inhibitor (DENV EC₅₀=4.79 μM, Vero CC₅₀>100 μM, SI>20.9). DENV-IN-4 can inhibit the expression level of DENV2 with concentration-dependence and reduce RNA-dependent RNA polymerase (RdRp) enzymatic activity. DENV-IN-4 has antiviral effect.

RNAP-σ interaction inhibitor1 (compound 5d) is an inhibitor of RNA polymerase-sigma factors interaction. RNAP-σ interaction inhibitor-1 exhibits the activity against Streptococci with MIC values of 1-2 µg/mL.

Simeprevir-¹³C,d₃ is the ¹³C- and deuterium labeled Simeprevir. Simeprevir is an oral, potent and highly specific hepatitis C virus (HCV) NS3/4A protease inhibitor with a K_i of 0.36 nM. Simeprevir inhibits HCV replication with an EC₅₀ of 7.8 nM. Simeprevir also potently suppresses SARS-CoV-2 replication and synergizes with Remdesivir. Simeprevir inhibits the main protease (Mpro) and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, and also modulates host immune responses.

CYP2C19-IN-1 (compound 20d) is a potent CYP2C19 inhibitor, possessing no hepatotoxicity and ames toxicity. CYP2C19-IN-1 inhibits RNA-dependent RNA polymerase (RdRP) with a K_i value of 6.16 µM. CYP2C19-IN-1 can be used in study of anti-ZIKV.

Favipiravir (T-705) sodium is an inhibitor of viral RNA polymerase (RNA polymerase), which is converted into its active form Favipiravir-ribofuranosyl-5′-triphosphate (RTP). Favipiravir-RTP inhibits the activity of influenza virus RNA-dependent RNA polymerase (RdRP) with an IC₅₀ of 341 nM.

2'-Deoxy-2'-fluoro-l-uridine is an L-nucleoside compound. 2'-Deoxy-2'-fluoro-l-uridine is a potent, selective viral RNA polymerase inhibitor, thereby inhibiting RNA virus replication.

POLRMT-IN-4 is a photoactivated mitochondrial RNA polymerase (POLRMT) inhibitor. POLRMT-IN-4 can be liberated from the photoactivatable prodrug upon irradiation, enables spatiotemporally precise inhibition and localized tissue selectivity. POLRMT-IN-4 disrupts mitochondrial transcription, impairs oxidative phosphorylation, and suppresses cancer cell proliferation. POLRMT-IN-4 can be used in research on various cancers, such as pancreatic cancer.

ε-Amanitin, a cyclic peptide isolated from a variety of mushroom species, potently binds to and inhibits the activity of RNA polymerase II.

Triptolide-6-succinate-β-D-glucose (Compound 2) is a glucose-conjugated derivative of Triptolide (HY-32735). Triptolide-6-succinate-β-D-glucose is a tumor-selective prodrug targeting glucose transporters ( GLUT). Triptolide-6-succinate-β-D-glucose can induce the degradation of the RPB subunit of RNA polymerase II. Triptolide-6-succinate-β-D-glucose inhibits the proliferation of HEK293T cells with an IC₅₀ value of 268 nM. Triptolide-6-succinate-β-D-glucose can be used for the research of cancer, such as prostatic cancer.

YH-0623 is an orally active mitochondrial RNA polymerase (POLRMT) inhibitor (IC₅₀ = 50.48 nM, Nanoluciferase Bioluminescence Resonance Energy Transfer (NanoBRET) assay). YH-0623 exhibits antiproliferative effects on 22Rv1 cells by reducing the expression of mitochondrial-related genes. YH-0623 inhibits 22Rv1 cell growth, colony formation, and the expression of OXPHOS-related proteins. YH-0623 significantly inhibits tumor growth in a prostate cancer xenograft mouse model. YH-0623 is indicated for prostate cancer research.

2'-(2-Nitrobenzyl)-ATP trisodium is a rATP analog. 2'-(2-Nitrobenzyl)-ATP trisodium acts as a transcription terminator, inhibiting further RNA chain elongation by T7 RNA polymerase.

RNAP-σ interaction inhibitor-2 (compound 7d) is an inhibitor of RNA polymerase-sigma factors interaction. RNAP-σ interaction inhibitor-2 exhibits the activity against S. aureus with MIC values of 2 µg/mL.

(Z)-Corallopyronin A is an isomer of Corallopyronin A (HY-N11622). Corallopyronin A is a polyketide natural product derived from myxobacteria and acts as a bacterial RNA polymerase (RNAP) inhibitor with antibacterial activity. Corallopyronin A binds to the switch region of RNA polymerase and allosterically blocks the transcription initiation process. Corallopyronin A exhibits in vitro antibacterial activity against Staphylococcus aureus, coagulase-negative staphylococci, Neisseria gonorrhoeae, and the filarial endosymbiont Wolbachia. (Z)-Corallopyronin A can be used for research related to bacterial infections.

RNA polymerase II-IN-2 is a RNA polymerase II inhibitor with a K_i value of 74.1 nM. RNA polymerase II-IN-2 inhibits Pol II-mediated transcription and induces cytotoxicity in mammalian cells. RNA polymerase II-IN-2 serves as a payload for antibody-drug conjugates (ADC) and is applicable for cancer research.

HNC-1664 is the orally active inhibitor for RNA-dependent RNA polymerase (RdRP). HNC-1664 exhibits broad-spectrum antiviral activity against coronavirus (SARS-CoV-2 wildtype and its mutants XBB.1.18, HK.3.1, BF.7.14, BA.1HCoV-229E, HCoV-OC43) and arenavirus. HNC-1664 exhibits anti-infectious activity in SARS-CoV-2 Delta infected mouse models.