ICA-1 / University of South Florida - LARVOL DELTA

Elacridar sensitizes liver cancer to the PKC-inhibitor ICA-1S (AACR 2024) - "This resistance inflection may be due to several factors including the activation of drug-efflux proteins. Thus, we proved that the introduction of an efflux pump inhibitor, Elacridar, sensitizes the liver cancer cells to ICA-1S, offsets the resistance of the liver cancer cells to ICA-1S at high concentrations, and enables ICA-1S to be effective in downregulating PKC-ι and decreasing cell growth of liver cancer cells."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor

Atypical protein kinases C-ζ and ι-inhibitors impede the growth of malignant gastric cancer cells (AACR 2024) - "Likewise, a downregulation of the apoptosis-related markers, Survivin and Caspase-3, was also illustrated in ζ-stat treated cells. Current, investigations include how these aPKC inhibitors, ICA-1S and ζ-stat, play into some of the well-established gastric cancer pathways to lead to cell deaths with techniques such as Western Blot analysis, Immunoprecipitation Assays and Flow cytometry."

Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BIRC5 • CASP3

PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3 (AACR 2024) - "Intravenous and oral administration of ICA-1S resulted in the reduction of tumor growth by approximately 30% in athymic nude mice for U-87 xenografts. Taken together, these results suggest that not only do aPKCs play a central role in GB progression, invasiveness, and cell survival, but that effective therapeutics can be developed to specifically target oncogenic aPKCs."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • AKT1 • CTNNB1 • JUN • MYC • PRRX1 • SMAD2 • SNAI1 • SNAI2 • STAT3

PKC-ι and 14-3-3 are crucial regulators of c-Raf and the Erk pathway in human medulloblastoma (AACR 2024) - "Treatment with ICA-1S was also shown to substantially decrease cellular invasion of Daoy and ONS-76 cells and induce apoptosis. Taken together, these data suggest that PKC-ι likely plays a critical role in the regulation of the c-Raf/Erk pathway, which controls the proliferation and invasion of human medulloblastoma."

Brain Cancer • Hematological Malignancies • Leukemia • Medulloblastoma • Oncology • Solid Tumor • FOS • MAP2K1 • MYC • RAF1 • STAT1 • STAT3

Osteoblasts alter their protein expression profile in the presence of prostate cancer cells to facilitate their invasion (AACR 2024) - "We are investigating the broader effects of four different nucleoside reverse transcriptase inhibitor (NRTI) analogs 5-fluoro-1-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (KBMD-E), 3-benzoyl-5-fluoro-1-((1S,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (KBMD-G), 1-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (KBMD-H) and 1-(5-hydroxymethyl)-2,5-dihydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (KBMD-S) along with aPKC specific inhibitors ICA-1S and ζ-Stat to develop as potential anti-cancer drugs...Upregulation of Caspase 8 with cleaved gasdermin D in prostate cells indicates an increase in pyroptosis. Our preliminary results suggest that all 6 compounds can be used to disrupt the main steps of prostate cancer bone metastasis which can be targeted to develop customized, tailored therapies for bone metastatic prostate cancer which merit further research."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP8 • CXCL1 • CXCL8 • IL1B • IL6 • JUN

PKC-iota specific inhibitor ICA-1S causes the degradation of mutant p53 in ovarian cancer cell lines (AACR 2024) - "Application of proteasome inhibitor MG-132 at a single dose of 0.5µM could not completely inhibit the degradation of mut53 and WTp53 in ICA-1S treated ES-2 cell line and HEY cell line, respectively, indicating the drug may be affecting the transcription of p53 as well. It is therefore postulated that aPKCɩ can phosphorylate p53, stabilizing it and may be affecting the transcription of p53 as well in those cell lines. Further research (kinase activity assay, immunoprecipitation, immunofluorescence) is going on to reveal the mode of this degradation."

Preclinical • Oncology • Ovarian Cancer • Solid Tumor • CDKN1A

Dual inhibition of atypical PKC signaling and PI3K/Akt signaling dysregulates c-Myc to induce apoptosis in clear cell Renal Cell Carcinoma. (PubMed, Front Oncol) - "We used combination of PI3K inhibitor- Alpelisib (BYL719) and ICA-1 (a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide). The decreased level of N-cadherin, p-vimentin, and vimentin and the increased level of E-cadherin confirm reduced malignancy. Therefore, implementing a combination of Alpelisib and a PKC-ι inhibitor is an effective approach to reducing cell proliferation, and invasion that eventually induces apoptosis and may be considered as a potential therapeutic option in ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AKT1 • CDH1 • CDH2 • MYC • VIM

Fenofibrate Ameliorates Retinal Pigment Epithelium Injury Induced by Excessive Fat Through Upregulation of PI3K/AKT Signaling. (PubMed, Drug Des Devel Ther) - "The application of fenofibric acid resulted in the inhibition of NOX4, 3-NT, TNFα, ICAM1 and VEGF expression in ARPE-19 cells treated with PA. Meanwhile, in vivo dosing of fenofibrate ameliorated the downregulated amplitudes of ERG c-wave in HFD-fed mice and suppressed the HFD-induced oxidative injury and inflammatory response in RPE tissues. Our results suggested that fenofibrate ameliorated RPE cell damage induced by excessive fat in vitro and in vivo, in part, through activation of the PI3K/AKT signaling pathway."

Journal • Inflammation • Oncology • ICAM1 • NOX4 • TNFA

Action potential conduction in the mouse and rat vagus nerve is dependent on multiple voltage-gated sodium channels (Na1s). (PubMed, J Neurophysiol) - "We studied the A- and C-waves of electrically-stimulated compound action potentials (CAP) of the mouse and rat vagus nerves with and without Na1 inhibitor administration: tetrodotoxin (TTX), PF-05089771 (mouse Na1.7), ProTX-II (Na1.7), ICA-121341 (Na1.1, Na1.3, Na1.6), LSN-3049227 (Na1.2, Na1.6, Na1.7) and A-803467 (Na1.8). Overall, our data demonstrate that multiple Na1 subtypes contribute to vagal CAPs, with Na1.7 and Na1.8 playing predominant roles and Na1.6 and Na1.2 contributing to a different extent based upon nerve fiber type and species. Inhibition of these Na1 may impact autonomic regulation of visceral organs."

Journal • Preclinical

Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin (AACR 2023) - "Current treatment strategies are surgical removal of cancerous parts and chemotherapy with platinum drugs (e.g. cisplatin, carboplatin) or taxols. Inhibition of ES-2 cell line with ICA-1S and ζ-stat also suggested that PKC-ι and PKC ζ play important roles in ovarian cancer and may augment traditional chemotherapy. Further study on the pathway affected by aPKC inhibitors combined with cisplatin would be investigated through WST, western blotting and immunoprecipitation assay."

Combination therapy • IO biomarker • Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • PI3K

Atypical protein kinase C inhibitors abrogate malignant breast cancer (AACR 2023) - "Hence, this project focused on utilizing aPKC inhibitors, ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide and - Stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid), on two malignant breast cancer cell lines (T47D and BT549) to observe the effect on cell proliferation...In addition, siRNA treatment will be applied to knockdown PKC- and PKC- and subsequent effect will be observed. In conclusion, PKC- and PKC- plays asignificant role on breast cancer, and further investigation will be conducted to analyze these roles, which will lead to the determination of a signaling pathway via which atypical protein Kinase C functions in breast cancer."

Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • BIRC5 • CASP3

A biophysical investigation into the binding interactions of novel anti-cancer inhibitors of atypical protein kinase C (aPKCs) (AACR 2023) - "Moreover, we show the chemical interactions of five novel anti-cancer inhibitors ICA-1S (Nucleosidic homolog) 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide), ICA-1T (Phosphorylated nucleosidic homolog of ICA-1S, [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate), ACPD (2-acetyl-1,3-cyclopentanedione), DNDA (3,4-diaminonaphthalene-2,7-disulfonic acid) and ζ(ZETA)-Stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid) to locate their regions of binding on the catalytic domain of the aPKCs (PKC- ι and PKC- ζ)...Moreover, we have applied the isothermal calorimetry method to understand the biophysical properties of the aPKCs in presence of these inhibitors. The observed biophysical properties of the protein and chemical shift perturbations in the amide backbone of the catalytic domain upon binding shed light on the molecular recognition process, binding characteristics, and atomic-level structural..."

Oncology

14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression (AACR 2023) - "We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and BE(2)-M17 cells: a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat)...Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-β pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research."

CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor • CDK7 • NF-κβ • SMAD2 • TGFB1 • VIM

PKC-ι is a simultaneous modulator of the sonic hedgehog and the FAK/paxillin pathways in medulloblastoma (AACR 2023) - "Our data demonstrated the effectiveness of atypical protein kinase C (aPKC) inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD), 3,4-diaminonapthalene-2,7-disulfonic acid (DNDA), 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S), and 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) to significantly decrease cell proliferation with increasing inhibitor concentration...Future studies will be conducted to determine the effect of aPKC inhibitors on additional downstream proteins in the FAK/paxillin pathway and cell cycle regulation by Western blotting. We will also be investigating the effect of the inhibitors on the migratory and invasive capacity of medulloblastoma by implementing wound-healing assays and Boyden chamber assays."

Brain Cancer • Hematological Malignancies • Leukemia • Medulloblastoma • Oncology • Solid Tumor

Oncogenic PKC-ι/PKC-ζ/14-3-3 and PKC-ι/PKC-ζ/Smad2/3 signaling cascades are crucial for increased invasiveness of Neuroblastoma cells (AACR 2022) - "The present study shows the downstream effects PKC-ι specific inhibitor 5-amino-1-(2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific inhibitor 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) on aPKCs, 14-3-3, p-14-3-3, Akt1, NF-κB p65, Smad2/3 and p-Smad2/3...Overall results suggest that aPKCs are crucial for increased invasiveness in NB. Results suggested that aPKC can be targeted to develop customized, tailored therapies for NB which merit further research."

Neuroblastoma • Oncology • Solid Tumor • AKT1 • CDH1 • RELA • SMAD2 • SNAI1 • VIM

A combination therapy of atypical protein kinase C inhibitors and phosphatidylinositol-3-kinase inhibitor reduces resistance & invasiveness in renal cell carcinoma (RCC) (AACR 2022) - "Treatment of ccRCC metastatic clear cells with a combination of aPKC inhibitor [8-hydroxynaphthalene-1, 3, 6-trisulfonic acid] ζ-stat, or ICA-1 and BYL 719 inhibits PKC ί/λ and PKC ζ with the downstream inhibition of c-Myc (a major protein controlling cell survival and cell cycle progression in RCC). Hence, combination therapy of Alpelisib and an aPKC inhibitor for metastatic ccRCC can reduce expression of multi drug resistance (MDR) proteins/efflux transporter P-gp and ABCG2. Therefore, a combination of Alpelisib and an aPKC inhibitor is an effective approach to reducing cell proliferation, invasion and resistance eventually inducing apoptosis."

Combination therapy • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ABCG2 • MYC

Prevalent PKC-ι/ζ signaling is crucial for apoptosis inhibition and invasiveness of glioblastoma through upregulation of Pdk1/Akt1/14-3-3 cascade and Smad2/3 (AACR 2022) - "Data confirmed that aPKC attenuation triggers multiple pro apoptotic signaling cascades through downregulation of Akt1, Pdk1, 14-3-3 and Smad2/3.We have used a novel PKC-ι specific inhibitor 5-amino-1-(2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific inhibitor 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) to conduct in-vivo experiments on murine models...Overall results suggest that aPKCs are crucial for increased invasiveness in GB. Results suggested that aPKC can be targeted to develop customized, tailored therapies for Glioblastoma which merit further research."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AKT1 • CDH1 • PDK1 • PRRX1 • SMAD2 • SNAI1 • SNAI2 • VIM

Role of NaV1.7 in Action Potential Conduction along Human Bronchial Vagal Afferent C-fibers. (PubMed, Br J Pharmacol) - "NaV1.7 blockers can prevent action potential conduction in the majority of vagal C-fibers arising from human bronchi. Blockers of NaV1.7 channels may therefore have value in inhibiting the responses to excessive airway C-fiber activation in inflammatory airway disease; responses that include coughing as well as reflex bronchoconstriction and secretions."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Contribution of tetrodotoxin-sensitive voltage-gated sodium channels (Na1) to action potential discharge from mouse esophageal tension mechanoreceptors. (PubMed, Am J Physiol Regul Integr Comp Physiol) - "The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. In summary, multiple Na1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus inhibition of individual Na1s would likely have minimal effect on afferent regulation of esophageal motility."

Journal • Preclinical • Gastrointestinal Disorder • Pain

[VIRTUAL] Inhibition of PKC-i signaling decreases the invasiveness of glioblastoma cells and sensitizes them to Temozolomide therapy (AACR-II 2020) - "[4-(5-amino-4-carbamoylimidazol-1-yl)-2, 3-dihydroxycyclopentyl] methyl dihydrogen phosphate also known as ICA-1 was used as a specific inhibitor of PKC-ι. Immunoprecipitation assay confirmed that that PKC-ι is associated with FAK and inhibition of PKC-ι led to decreased FAK phosphorylation. Our studies suggest that targeting PKC-ι might be an important therapeutic approach in the treating GBM."

Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • PXN

[VIRTUAL] PKC-ζ plays a critical role as a tumor suppressor in the downregulation of oncogenic PKC-ι induced EMT in glioblastoma cells (AACR-II 2020) - "On the other hand PKC-ζ plays a critical role as a tumor suppressor. Therefore development of PKC-ι specific inhibitor ICA-1S would generate an effective way to mitigate GB."

Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CDH1 • FOXO1 • IKZF2 • VIM

[VIRTUAL] Atypical PKC inhibitors ICA-1S and ζ-Stat show inhibition of neuroblastoma cell proliferation (AACR-II 2020) - "Ongoing experiments include the analysis of tumors collected from mouse models to ascertain the effects of the drugs in vivo as well as the analysis of human tumor samples to ascertain the expression of aPKCs and other markers in patient populations. Experiments also include the use of gene expression knockdowns to compare with the effects from the inhibitors as well as the use of microscopy techniques; fluorescent and electron miscopy to observe the localization of mesenchymal and proliferative markers."

Neuroblastoma • Oncology • Solid Tumor • CDK2 • VIM