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- | Journal: Polycystin-1 regulates cell proliferation and migration through AKT/mTORC2 pathway in a human craniosynostosis cell model. (Pubmed Central) - Apr 13, 2022
PC1 inhibition also induced activation of AKT, exhibiting elevated phospho (p)-AKT (Ser473) levels, but not 4EBP1 or p70S6K activation. Our findings indicate that PC1 may act as a mechanosensing molecule in cranial sutures by modulating osteoblastic cell proliferation and migration through the PC1/AKT/mTORC2 cascade with a potential impact on the development of non-syndromic craniosynostosis.
- | docetaxel / Generic mfg.
Journal: TFAP2C-Mediated lncRNA PCAT1 Inhibits Ferroptosis in Docetaxel-Resistant Prostate Cancer Through c-Myc/miR-25-3p/SLC7A11 Signaling. (Pubmed Central) - Apr 12, 2022
Finally, transcription factor AP-2 gamma (TFAP2C) activated PCAT1 expression at the transcriptional level to reduce ferroptosis susceptibility and enhance chemoresistance. Collectively, our findings demonstrated that TFAP2C-induced PCAT1 promotes chemoresistance by blocking ferroptotic cell death through c-Myc/miR-25-3p/SLC7A11 signaling.
- | Journal: PCK1 regulates neuroendocrine differentiation in a positive feedback loop of LIF/ZBTB46 signalling in castration-resistant prostate cancer. (Pubmed Central) - Mar 11, 2022
Collectively, our findings demonstrated that TFAP2C-induced PCAT1 promotes chemoresistance by blocking ferroptotic cell death through c-Myc/miR-25-3p/SLC7A11 signaling. Our study uncovers LIF/ZBTB46 signalling activation as a key mechanism for upregulating PCK1-driven glucose metabolism and neuroendocrine differentiation of CRPC, which may yield significant improvements in prostate cancer treatment after ADT using PCK1 inhibitors.
- mitomycin / Generic mfg.
ENPP1 inhibitor ZX-8177 enhances anti-tumor activity of conventional therapies by modulating tumor microenvironment (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6945;
Combination of Mitomycin C (0.5 mg/kg, i.p., BIW) and ZX-8177 (2 mg/kg, i.p., BID) in CT-26 model yielded synergistic anti-tumor efficacy (increased >30% TGI)...TGI of anti-PD-L1 antibody vs. combo treatment is 53% vs. 75%, p < 0.05. ZX-8177 has a favorable DMPK and safety pharmacology profile to support it as a clinical candidate for further development.
- Discovery of potent and orally available ENPP1 inhibitors activating STING Pathway and induces tumor growth inhibition in syngeneic tumor model (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6925;
IBS725 has shown good oral bioavailability in mouse and rat, is well tolerated and efficacious in MC38 colon cancer model both as a single agent as well as in combination with Checkpoint inhibitors. The studies on further characterization of ENPP1 inhibitors and their mechanism of action are ongoing and the results will be reported in due course.
- | Journal, IO biomarker: Development of a High-Throughput Assay to Identify Inhibitors of ENPP1. (Pubmed Central) - Feb 24, 2022
ENPP1 showed a 20-fold selectivity for 2'3'cGAMP compared with 2'3'c-diGMP and showed no activity with 3'3'c-diAMP. The Transcreener AMP/GMP Assay should prove to be a valuable tool for the discovery of ENPP1 lead molecules.
- | thioguanine / Generic mfg.
Journal: Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy. (Pubmed Central) - Feb 24, 2022
The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.
- | Journal: The cardiomyocyte disrupts pyrimidine biosynthesis in non-myocytes to regulate heart repair. (Pubmed Central) - Feb 19, 2022
We identified ENPP1 inhibitors on small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in non-myocyte cells, augmented cardiac repair and post infarct heart function. These observations demonstrate that the cardiac muscle cell by releasing adenine and specific nucleosides after heart injury regulates pyrimidine metabolism in non-muscle cells and provide insight into how inter-cellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
- | Journal: If these myocytes could talk, they would speak the language of metabolites. (Pubmed Central) - Feb 9, 2022
These findings have clear therapeutic implications, as the authors identified a small molecular inhibitor of ENPP1 that improved post-MI outcomes in mice. These exciting data provide impactful mechanistic information that advance the field's understanding of cardiac repair and remodeling.
- | Journal, Myeloid-derived suppressor cells: Tumor ENPP1(CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer. (Pubmed Central) - Jan 29, 2022
Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
- [VIRTUAL] Orally available ENPP1 inhibitor, TXN10128, restores STING activation in tumor microenvironment and confers anti-tumor responses in combination with immune checkpoint blockade () - Sep 30, 2021 - Abstract #AACRNCIEORTC2021AACR_NCI_EORTC_450;
- | Journal: Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents. (Pubmed Central) - Jul 17, 2021
In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.
- | Journal: Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP. (Pubmed Central) - Jul 10, 2021
Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics.
- || furosemide / Generic mfg., artemether / Generic mfg.
PK/PD data, Preclinical, Journal: Choline and PEG dually modified artemether nano delivery system targeting intra-erythrocytic Plasmodium and its pharmacodynamics in vivo. (Pubmed Central) - Apr 28, 2021
Moreover, in vitro and in vivo studies that evaluated antimalarial activity suggested that CD-PEG-ARM-NLC exhibited higher antimalarial activity in comparison to ARM-NLC and PEG-ARM-NLC. These findings suggested that choline and PEG dually modified NLC could be promising preparations for the production of hydrophobic antimalarial drugs, particularly for ARM.
- | Germanin (suramin) / Optimum Therap
Journal: Evaluation of sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as inhibitors of nucleotide pyrophosphatases/phosphodiesterases and anticancer agents. (Pubmed Central) - Mar 30, 2021
Moreover, cytotoxic evaluation against MCF-7 and HT-29 cancer cell lines revealed that compound 1r is the most cytotoxic towards MCF-7 cell line with IC value of 0.19 µM. Compound 1r is more potent and selective against cancer cells than normal cells (WI-38) as compared to doxorubicin.
- | Journal: Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. (Pubmed Central) - Mar 27, 2021
Boosting extracellular cGAMP with ENPP1 inhibitors synergized with IR to delay tumor growth. In conclusion, extracellular cGAMP is an anti-cancer immunotransmitter that could be harnessed to treat cancers with low immunogenicity.
- [VIRTUAL] Discovery of novel potent and orally bioavailable small-molecule inhibitors of ENPP1 to stabilize cGAMP and ATP in the tumor microenvironment and boost anti-tumor immunity (Channel 07) - Mar 11, 2021 - Abstract #AACR2021AACR_1858;
An update on in vivo efficacy data in a range of ENPP1-positive tumor models will be provided during the presentation. These novel orally bioavailable ENPP1 inhibitors unleash local, TME-restricted, innate immune activation, and hold the promise to overcome the current limitations of direct STING agonists.
- [VIRTUAL] Potent ENPP1 inhibitors activating STING pathway in tumor microenvironment () - Mar 11, 2021 - Abstract #AACR2021AACR_479;
No body weight loss was observed at this efficacious dose during treatment. The studies on further characterization of ENPP1 inhibitors and their mechanism of actions are ongoing and the results will be reported in due course.
- | Journal: Re-awakening Innate Immune Signaling in Cancer: The Development of Highly Potent ENPP1 Inhibitors. (Pubmed Central) - Mar 5, 2021
Here, Carozza et al. (2020b) report potent and selective inhibitors of ENPP1, a negative regulator of innate immune signaling, which are shown to potentiate anti-tumor immune responses.
- | Germanin (suramin) / Optimum Therap
Journal: Synthesis, biological evaluation, and docking studies of new pyrazole-based thiourea and sulfonamide derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase. (Pubmed Central) - Mar 2, 2021
They were much more potent than the reference standard inhibitor, suramin (IC values against ENPP1 and -3 were 7.77 and 0.89 µM, respectively)...Compound 1e was active against all the three cancer cell lines, however, showed preferential cytotoxicity against MCF-7 (IC = 16.05 µM), which is comparable to the potency of cisplatin...The relative selectivity and potency of the inhibitors was justified by molecular docking studies. All the docked structures showed considerable binding interactions with amino acids residues of active sites of ENPP isoenzymes.
- | Journal: Procyanidin A1 Alleviates Inflammatory Response induced by LPS through NF-κB, MAPK, and Nrf2/HO-1 Pathways in RAW264.7 cells. (Pubmed Central) - Oct 30, 2020
Meanwhile, PCA1 inhibited the production of intracellular ROS and alleviated the depletion of mitochondrial membrane potential in vitro. Collectively, our data indicated that PCA1 exhibited a significant anti-inflammatory effect, suggesting that it is a potential agent for the treatment of inflammatory diseases.
- [VIRTUAL] ENPP1 Regulates UV Light Triggered Type I Interferon Response in the Skin (Feed 7) - Oct 8, 2020 - Abstract #ACRARHP2020ACR_ARHP_1566;
The cGAS requirement for ISG spreading and augmented IFN-I response following ENPP1 inhibition, indicate that extracellular cGAMP amplifies skin ISG induction following UV exposure. The reduced ISG expression in albino compared to B6 mice is likely explained by UV induced ENPP1 expression which reduces extracellular cGAMP.
- | paclitaxel / Generic mfg.
Biomarker, Journal: Long noncoding RNA PCAT1, a novel serum-based biomarker, enhances cell growth by sponging miR-326 in oesophageal squamous cell carcinoma. (Pubmed Central) - Jul 7, 2020
Moreover, knockdown of PCAT1 arrested the cell cycle at G2/M phase, reduced the expression of cyclin B1 and CDC2, and caused cells to be more sensitive to paclitaxel...In addition, we discovered that PCAT1 was present in ESCC cell-derived exosomes, was higher in the serum of ESCC patients than those of healthy volunteer donors, and promoted cell growth through exosomes. Thus, our data indicate that PCAT1 promotes ESCC cell proliferation by sponging miR-326 and may serve as a non-invasive biomarker for ESCC.
- | Journal: Long non-coding RNA PCAT1 promotes cell migration and invasion in human laryngeal cancer by sponging miR-210-3p. (Pubmed Central) - Jun 25, 2020
Thus, our data indicate that PCAT1 promotes ESCC cell proliferation by sponging miR-326 and may serve as a non-invasive biomarker for ESCC. PCAT1 was first identified as a novel oncogene in LC and could promote LC cell migration and invasion by sponging miR-210-3p.
- | Biomarker, Journal: Development of an ENPP1 fluorescence probe for inhibitor screening, cellular imaging and prognostic assessment of malignant breast cancer. (Pubmed Central) - Jun 18, 2020
We further found that ENPP1 mRNA expression in tissue samples from patients with triple-negative breast cancer was significantly inversely related to recurrence-free survival (RFS) and overall survival (OS), and TG-mAMP assay revealed a significant difference in ENPP1 activity between ENPP1 high-expressing and ENPP1 low-expressing samples. Our results suggest that TG-mAMP assay might be a rapid and inexpensive tool for predicting the prognosis of patients with malignant breast cancers.
- SR8541A is a potent inhibitor of ENPP1 and exhibits dendritic cell mediated antitumor activity (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_2449;
The results from these studies along with physiochemical properties and tumor model data will be presented. The promising physiochemical properties make it a strong candidate for clinical studies.
- || Review, Journal: ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors-A STING in the Tale of ENPP1. (Pubmed Central) - Apr 4, 2020
This emerging role of ENPP1 has placed this "old" enzyme at the frontier of immunotherapy. This review highlights the roles played by ENPP1, the mechanism of cGAMP hydrolysis by ENPP1, and small molecule inhibitors of ENPP1 with potential applications in diverse disease states, including cancer.
- | Journal: Polycystin-1 Inhibits Cell Proliferation through Phosphatase PP2A/B56α. (Pubmed Central) - Mar 26, 2020
In addition to the phosphorylated S6 and 4EBP1, B56α was also downregulated by PC1 and PC1-5TMC. Furthermore, the downregulation of B56α, which may be mediated by mTOR but not AKT, can account for the dependence of PC1-inhibited proliferation on PP2A.
- | Journal: Identification of adenine-N9-(methoxy)ethyl-β-bisphosphonate as NPP1 inhibitor attenuating undesired NPPase activity in human osteoarthritic chondrocytes. (Pubmed Central) - Feb 24, 2020
Thus, 10 is a dual NPP1/CD73 inhibitor, which could not only be of interest for treating CPPD deposition disease and calcific aortic valve disease but may also be considered for the immunotherapy of cancer. Compound 10 proved to be a promising inhibitor, which almost completely reduces NPPase activity in human osteoarthritic chondrocytes at a concentration of 100 μM.
- | Journal: Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-β-phosphate scaffold. (Pubmed Central) - Feb 21, 2020
A correlation was observed between the activities of the compounds and the number of H-bonds and salt bridges formed between the inhibitors and NPP1 binding site residues. Uracil-N1-(methoxy)ethyl-β-P-dithio, P-methylene tri-phosphate, 17, was identified as the most potent, selective, and non-toxic NPP1 inhibitor among the tested analogs, and may be used as a lead structure for further drug development.
- | Journal: Role of PKR in the Inhibition of Proliferation and Translation by Polycystin-1. (Pubmed Central) - Dec 23, 2019
Because suppressed PKR-eIF2α signaling/activity by PC1 would stimulate, rather than inhibit, the proliferation and translation, we examined the effect of dominant negative PKR mutant K296R that has no kinase activity and found that it enhances the inhibition of proliferation and translation by PC1. Thus, our study showed that inhibition of cell proliferation and protein synthesis by PC1 is mediated by the total expression but not the kinase activity of PKR, possibly through physical association.
- | Journal: Adenine-(methoxy)-ethoxy-P-dithio-triphosphate inhibits pathologic calcium pyrophosphate deposition in osteoarthritic human chondrocytes. (Pubmed Central) - Dec 22, 2019
Analog 8 was not toxic to cultured chondrocytes at 100 μM. Therefore, 8 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.
- | Journal: Knockdown of long non-coding RNA PCAT1 in glioma stem cells promotes radiation sensitivity. (Pubmed Central) - Nov 27, 2019
In addition, silencing PCAT1 could increase the expression of miR-129-5p and decrease the expression of HMGB1. PCAT1 was overexpressed in GSCs and played a facilitating role in radiation resistance.
- fasudil / Generic Mfg.
Polycystin 1 Regulates Actomyosin Contraction and the Cellular Response to Extracellular Stiffness (143, Walter E. Washington Convention Center) - Oct 14, 2019 - Abstract #KIDNEYWEEK2019KIDNEY_WEEK_5143;
Notably, treatment with this compound ameliorates disease progression. Conclusion Our data suggest a possible direct role for PC-1 as a mechanosensor able to negatively regulate the cellular response to extracellular stiffness.
- ENPP1 antagonists in combination with radiation or checkpoint inhibitors demonstrate antitumor activity in syngeneic mice models of pancreatic adenocarcinoma, neuroblastoma, TNBC, and colon cancer (Prince George's Exhibition Halls AB) - Oct 2, 2019 - Abstract #SITC2019SITC_1017;
Lead molecule ANG-1623 has desirable properties of a drug and was subsequently tested in syngeneic mice tumor models: 4T1, Panc02, Neuro-2a, and MC38, where it was administered subcutaneously for 7 to 28 days. The drug was well tolerated and demonstrated significant anti-tumor activity alone or in combination with radiotherapy and/or anti-PD-L1.
- ENPP1 antagonists in combination with radiation or checkpoint inhibitors demonstrate antitumor activity in syngeneic mice models of pancreatic adenocarcinoma, neuroblastoma, triple negative breast cancer, and colon cancer () - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_288;
Lead molecule ANG-1623 has desirable properties and characteristics of a drug and was subsequently tested in syngeneic mice tumor model Panc02, Neuro-2a, 4T1 and MC38, administered subcutaneously for 7 to 28 days. The drug was well tolerated and demonstrated significant anti-tumor activity alone or in combination with radiotherapy and/or anti-PD-L1.