Table 3 Transcriptional co-activators and their small molecule inhibitors: pathological perspective
Co-activator | Small molecule inhibitor | Disease/Model of investigation | Mechanism of inhibitor action | Ref. |
|---|---|---|---|---|
YAP/TAZ | Cerivastatin | NSCLC | The mevalonate pathway-associated rate limiting enzyme inhibitor Cerivastatin, promoted cytoplasmic retention and subsequent degradation of YAP | |
Dasatinib | TNBC | SRC kinase activity is essential for YAP/TAZ activation. Dastinib inhibits SRC kinase which further inhibited nuclear localization of YAP/TAZ and decreased YAP/TAZ-TEAD-dependent reporter activity | ||
Fluvastatin | TNBC | Fluvostatin-mediated inhibition of HMG-CoA reductase leads to YAP/TAZ inactivation and halted nuclear translocation through disrupted geranylgeranylation of RhoA | ||
DC-TEADin02 | HEK293T and HCT 116 cells | Palmitoylation of TEAD is important for stability and interaction with YAP/TAZ. DC-TEADin02 is a vinylsulfonamide derivative and a covalent TEAD autopalmitoylation inhibitor | ||
Fenamate | Glioblastoma | Use of a chloromethyl ketone substitution to link fenamate with TEAD disrupts the YAP-TEAD interaction | ||
Alkylthio-triazole scaffold | HeLa, JHH7 and HuH7 cell lines | These compounds occupy palmitate-binding pocket and prevent interaction between YAP/TAZ and TEADs | ||
K-975 | Malignant pleural mesothelioma | Binds to Cys359 in PBP via an acrylamide structure to inhibit YAP/TAZ-TEAD interaction | ||
TEAD destabilizers | Not specified | Bind to PBP to destabilize TEAD conformation through in situ unfolding thereby preventing YAP/TAZ-TEAD interaction | ||
MSC-4106 | NCI-H226 tumor xenograft model | Prevents TEAD1/ TEAD3 auto-palmitoylation to inhibit activity of YAP/TAZ | ||
Verteporfin (VP) | NSCLC | Increases erlotinib sensitivity in H1975 cells. In combination with erlotinib, VP reduced invasion, migration and sphere-forming ability. | ||
Verteporfin (VP) | Liver cancer | Verteporfin-mediated inhibition of YAP/TAZ signaling significantly improved transcatheter arterial chemoembolization in transplanted hepatocellular carcinoma (HCC) | ||
Verteporfin (VP) | Gastric cancer | VP disrupts YAP/TAZ-TEAD interaction to decrease the pool of gastric cancer stem cells. | ||
Verteporfin (VP) | Head and neck cancer (HNSCC) | VP suppresses proliferation and metastasis by inhibiting YAP1. Verteporfin in combination with melatonin was also found to suppress survival and maintenance of head and neck cancer stem cells. | ||
Verteporfin (VP) | Breast cancer | Independent of light activation, VP mediated Caspase-9 cleavage and PARP cleavage induced apoptosis in the cells of various breast cancer subtypes by inhibiting YAP. Nano-encapsulated verteporfin in combination with combretastatin and paclitaxel inhibited breast cancer stem cells, bulk cancer cells, and angiogenesis. | ||
Pazopanib | TNBC | Pazopanib inhibits RHOA activity by inhibiting VEGFR and PDGFR, thereby promoting inhibitory phosphorylation of YAP/TAZ and their subsequent proteosomal degradation | ||
GNE-7883 | YAP/TAZ-dependent cancer cells like MDA-MB-231 NCI-H226, Detroit 562, HCC1576 | Mediates allosteric inhibition of YAP/TAZ-TEAD interaction by binding to TEAD lipid pocket | ||
YAP/TAZ inhibitor-1 | HER2-Positive Breast Cancer | Inhibits YAP/TAZ to reverse Trastuzumab resistance | ||
Atorvastatin and zoledronic acid (YAPPETIZER) | TNBC | Inhibits YAP/TAZ expression via mevalonate pathway (Phase II clinical trials; NCT03358017) | ||
HDAC inhibitors (Entinostat)+ Molibresib besylate (BET inhibitor) | Advanced and refractory solid tumors and lymphomas | This drug combination is in Phase I clinical trial (NCT03925428) and its exploratory objective includes checking of YAP activity after drug treatment | ||
Benzisothiazole-dioxide scaffold | Malignant pleural mesothelioma, lung cancer, breast cancer | Disrupts YAP/TEAD interaction by binding to TEAD surface | ||
VT103, VT104, VT105, VT106, and VT107 | Mesothelioma cell lines | Inhibit TEAD auto-palmitoylation | ||
Cytochalasin-D | Melanoma | Inhibits actin polymerization and promotes cytoplasmic retention of YAP/TAZ | ||
BET | JQ1 | TNBC | TNBC cell lines show growth inhibition when treated with JQ1 | |
JQ1 | Colorectal cancer (CRC) | JQ1 synergized with PD-1 blockade and enhanced anti-tumor activity by remodeling the immunosuppressive niche | ||
JQ1 | SCLC | Blocks NEUROD1 transactivation | ||
OTX-015/JQ1 | Liver cancer | Both the BET inhibitors downregulated HCC migration by inhibiting SMARCA4 | ||
JQ1 | Esophageal cancer | JQ1 prevents YAP1 activity by abolishing the interaction of BRD4 with YAP1 promoter | ||
JQ1 | Stomach cancer | JQ1 inhibits RUNX2/NID1 signaling to inhibit gastric cancer progression | ||
JQ1 | Cervical cancer | JQ1 inhibits BRD4 to sensitize cervical cancer cells to radiotherapy and inhibits the Plk1-Mutant Trp53 Axis. | ||
JQ1 | HNSCC | Therapeutic targeting of BRD4 is a potent anti-cancer strategy. | ||
ABBV-075 | HCC | Inhibit proliferation and migration of HCC | ||
BET-IN-8 (Compound 27) | Sepsis | BET-IN-8 (2-((2-methylbenzyl) thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile) is an effective bromodomain inhibitor of BRD4 which reduces pro-inflammatory factors expression | ||
BET bromodomain inhibitor 2 | Not specified | It is a N-Methylpyrrolidone compound which acts as a mimetic of acetyl-lysine and has enhanced affinity as inhibitor of BRD4 | ||
BET-IN-12 | TNBC | This BET-inhibitor is a triazole-containing carboline derivative (2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol) that has potent anti-tumor activity even at low doses | ||
GSK1324726A (I-BET726) | Neuroblastoma | Selective inhibitor of BRD2, BRD3, and BRD4, which downregulates the expression of MYCN and BCL2. | ||
SDR-04 | Cancer cell lines | It is a 3-methyl-1H-indazole derivative that is selective to BRD4 and mediates anti-proliferative activity by preventing the activation of BRD4 targets like c-MYC | ||
BRD4 Inhibitor-19 | U266 cancer cells | It is a 3,5-dimethylisoxazole derivative that is a potent inhibitor of BRD4 | ||
CF53 | Leukemia, Breast cancer | Orally active bromodomain and extra-terminal (BET) protein inhibitor | ||
BET + CBP/p300 | NEO2734 | NUT midline carcinoma (NMC) | The Dual inhibitor of BET and CBP/p300 bromodomain imparted greater proliferation inhibition and tumor regression | |
XP-524 | Pancreatic ductal adenocarcinoma | XP-524 inhibited KRAS/MAPK signaling | ||
CBP/p300 | I-CBP112 hydrochloride | Leukemia | Acts as a competitive inhibitor to the acetyl-lysine protein-protein interaction and prevents self-renewal of acute myeloid leukemia cells. | |
A-485 | NSCLC | A spiro-oxazolidinedione which targets and inhibits the HAT domain of CBP/p300 and reduces histone acetylation marks thereby restricts lung cancer cell proliferation through autophagic pathway activation | ||
Garcinol | Esophageal cancer | It is a poly-isoprenylated benzophenone derivative from the rind of Garcinia indica fruit and is found to inhibit p300 HAT activity by affecting the lysosomal pathway | ||
Anacardic acid | Colorectal cancer | It is a natural HAT inhibitor of p300 and PCAF which is extracted from cashew nut shell liquid. | ||
Lys-CoA | Melanoma | Selective synthetic inhibitor of p300 HAT activity | ||
B026 | Leukemia | A potent CBP/p300 small molecule inhibitor that achieved significant dose dependent tumor growth inhibition in MV-4-11 xenograft leukemia mice model | ||
YO8197 | Prostate cancer | A novel 1-(indolizin-3-yl) ethenone derivative selectively targets bromodomain of CBP/p300 in prostate cancer cell lines and significantly downregulates cMYC and ERG. | ||
Nordihydro-guaiaretic acid (NDGA) | HEK293T, HeLa, MEF | It is a natural p300 acetyltransferase activity inhibitor which has been reported to increase lifespan in both flies and mice and induces autophagy. | ||
C646 | Lung cancer | A selective small molecule inhibitor of p300 has been shown to radiosensitize lung cancer cell lines by inducing mitotic catastrope | ||
FT-6876 | Breast Cancer | Selective bromodomain inhibitor of CBP/p300 which inhibits acetylation of H3K27Ac at specific promoter sites | ||
CCS1477 (Inobrodip) | Prostate cancer, multiple myeloma | Bromodomain inhibitor of CBP/p300 | ||
Melatonin | Breast Cancer | Inhibits p300 activity | ||
BAP1 | iBAP-II | SCLC | Disrupts BAP1/ASXL3/BRD4 epigenetic axisand inhibits small cell lung cancer cell viability and growth in vivo | |
CRTC2 | Artepillin C | Obesity | Natural compound from propolis, inhibits CREB-CRTC2 axis and reduces lipid levels, enhances insulin sensitivity and decreases fasting glucose levels | |
A57 | Obseity | Artepillin C derivative. Higher inhibitory action against CREB-CRTC2 interaction | ||
PC4 | AG-1031 | NSCLC | Inhibits ds DNA binding activity of PC4 | |
DDX5 | RX-5902 | Renal cell cancer, pancreatic carcinoma, advanced solid tumors, breast cancer | A 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine that binds to p-tyr-593 of DDX5 and inhibits its ATPase activity. It is in phase I/II clinical trial. NCT02003092 | |
Simvastatin | Renal cell carcinoma (RCC) | Inhibits DDX5 and upregulates DUSP5 to inhibit RCC proliferation and metastasis | ||
TRIM24 | Acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors | Not specified | TRIM24 bromodomain inhibitor | |
MRTFs | CCG-222740 | Pancreatic adenocarcinoma | Inhibits RHO/MRTF pathway and modulates inflammatory activity | |
BCL9/BCL9L | Carnosic Acid | CRC | Disrupts β-catenin/BCL9 protein–protein interaction | |
SET7 | Cyproheptadine | Monocytes | In monocytes, cyproheptadine inhibits SET-7 induced persistent activation of malate dehydrogenase and succinate dehydrogenase and thereby, disrupts mitochondrial homeostasis. | |
SET7 | Cyproheptadine | Breast Cancer | In breast cancer, cyproheptadine destabilizes ERα-mediated gene activation |
