- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Targeting Gardos Channel to Regulate Lipid Scrambling in Red Blood Cells (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_6516;
Although Gardos inhibition is a promising strategy to decouple PIEZO1-TMEM16F interaction and prevent PS exposure, Senicapoc is not a suitable Gardos inhibitor for this purpose due to its unknown off-target effect. More specific Gardos inhibitors are needed to prevent PS exposure in red cell disorders.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Review, Journal: Potassium dynamics in sickle cell anemia: clinical implications and pathophysiological insights. (Pubmed Central) - Oct 3, 2024
Additionally, hydration therapy plays a crucial role in maintaining electrolyte balance and preventing RBC dehydration. A comprehensive approach that includes monitoring and correcting electrolyte imbalances, along with standard treatments like hydroxyurea and blood transfusions, is essential for effective disease management.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial completion date, Trial primary completion date: Senicapoc in Alzheimer's Disease (clinicaltrials.gov) - Sep 19, 2024
P2, N=55, Recruiting,
A comprehensive approach that includes monitoring and correcting electrolyte imbalances, along with standard treatments like hydroxyurea and blood transfusions, is essential for effective disease management. Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Prothrombotic mechanisms associated with enhanced venous thrombosis in sickle cell trait (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1879;
This is associated with shortening of the Russell Viper Venom time, indicative of phosphatidylserine-dependent prothrombinase activity (Figure 1D). The weight of thrombi formed 24 hours after IVC stasis was significantly increased (p < 0.01) in AS mice (n=8) compared to AA controls (n=7).
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial completion: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Feb 22, 2024
P1/2, N=5, Completed,
The weight of thrombi formed 24 hours after IVC stasis was significantly increased (p < 0.01) in AS mice (n=8) compared to AA controls (n=7). Recruiting --> Completed
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: IK Channel-Independent Effects of Clotrimazole and Senicapoc on Cancer Cells Viability and Migration. (Pubmed Central) - Nov 29, 2023
Neither clotrimazole nor senicapoc altered the intracellular Ca concentration. These results suggest that the effects of IK blockers on cancer cells are not strictly dependent on a robust presence of the channel in the plasma membrane, but they might be due to off-target effects on other cellular targets or to the blockade of IK channels localized in intracellular organelles.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Validation of Townes As Mice As a Model of Chronic Kidney Disease and Venous Thrombosis Associated with Sickle Cell Trait (SDCC - Room 33) - Nov 3, 2023 - Abstract #ASH2023ASH_3237;
Senicapoc, an oral Gardos channel inhibitor, was administered twice daily (20mg/kg, bid) for 2 weeks to prevent AS RBC dehydration and subsequent sickling...In aggregate, our data demonstrate that Townes AS murine nephropathy closely mimics the renal abnormalities (impaired urinary concentration and albuminuria with later onset loss of GFR) described in humans with SCT. Furthermore, we have established a mouse model of the venous thrombotic complications associated with SCT and have demonstrated that hypoxia-induced sickling of RBCs may contribute to enhanced VT observed in AS mice.
- |||||||||| Biologic Assessment of RBC Biology and Neutrophil Activation: Correlation with Sickle Cell Disease Activity (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_1521;
On the other hand, higher HbF levels were associated with lower admission rates for VOE and a trend toward lower levels of neutrophil activation. This suggests that higher HbF, beyond its ability to reduce sickling, also alters other biological characteristics of SS RBCs and is accompanied by reduction in the inflammatory nature of SCD, thereby contributing to a decrease in VOE frequency.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: Repurposing the K3.1 Blocker Senicapoc for Ischemic Stroke. (Pubmed Central) - May 7, 2023
Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial primary completion date: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Apr 21, 2023
P1/2, N=6, Recruiting,
We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke. Trial primary completion date: Apr 2023 --> Dec 2023
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Review, Journal: Pancreatic K3.1 channels in health and disease. (Pubmed Central) - Mar 15, 2023
We are also giving a perspective for the use of a fluorescently labeled derivative of the K3.1 blocker senicapoc as a tool to monitor channel distribution in pancreatic tissue. In summary, modulating K3.1 channel activity is a useful strategy for exo-and endocrine pancreatic disease but further studies are needed to evaluate its clinical suitability.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: Imaging of KCa3.1 channels in tumor cells with PET and small-molecule fluorescent probes. (Pubmed Central) - Nov 1, 2022
The [18F]fluoroethyltriazolyl substituted senicapoc was used as positron emission tomography (PET) tracer and showed promising properties for imaging of KCa3.1 channels in lung adenocarcinoma cells in mice...Due to the methoxy moiety at the B-atom and the additional oxyethylene unit in the spacer, 9b exhibits higher polarity, which improves solubility and handling without reduction of fluorescence quantum yield. Docking studies using a cryo-electron microscopy (EM) structure of the KCa3.1 channel confirmed the interaction of 9a and 9b with a binding pocket in the channel pore.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: Functional expression of mitochondrial K3.1 channels in non-small cell lung cancer cells. (Pubmed Central) - Oct 18, 2022
Measurements of the mitochondrial membrane potential with TMRM reveal a hyperpolarization following the inhibition of K3.1 channels with the cell-permeable blocker senicapoc...The hyperpolarization of the mitochondrial membrane potential is accompanied by an increased generation of ROS in NSCLC cells. Collectively, our results provide firm evidence for the functional expression of K3.1 channels in the inner membrane of mitochondria of NSCLC cells.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Effects of KCNN4 Blockade With Senicapoc in Kidney Cell-Based Assays and a Mouse Model of Renal Inflammation and Fibrosis (Exhibit Hall, Orange County Convention Center, West Building) - Oct 13, 2022 - Abstract #KIDNEYWEEK2022KIDNEY_WEEK_1109;
Conclusion In summary, while KCNN4 may play a role in kidney disease, the PK profile of Senicapoc makes it not suitable for target validation studies in rodents. A compound with better exposure profile is needed in order to properly study the effects of KCNN4 blockage in a rodent disease model.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: The erythroid K-Cl cotransport inhibitor [(Dihydroindenyl)oxy]acetic acid (DIOA) blocks erythroid Ca-activated K channel KCNN4. (Pubmed Central) - Sep 2, 2022
Among standard inhibitors of KCC-mediated K-Cl cotransport, only [(dihydroindenyl)oxy]acetic acid (DIOA) has been reported to lack inhibitory activity against the related bumetanide-sensitive erythroid Na-K-2Cl cotransporter NKCC1/SLC12A2...RosettaLigand docking experiments identified a potential binding site for DIOA in the fenestration region of human KCa3.1. We conclude that DIOA at concentrations routinely used to inhibit K-Cl cotransport can also block the KCNN4/KCa3.1 Gardos channel in normal and sickle red cells.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: Enhancement of Endothelial KCa Channel Activity as a Novel Strategy to Oppose Atherosclerosis. (Pubmed Central) - May 14, 2022
While both SKA-31 and senicapoc improved aortic endothelial function, neither drug decreased plaque formation or aortic stiffness, perhaps due to the later onset of these events in the progression of atherosclerotic pathology. We will investigate this likelihood by feeding Apoe mice a high fat diet to accelerate the development of plaque formation and arterial stiffness to determine the effects of both drug treatments on these later stages of atherosclerosis.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Preclinical, Journal: Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (K3.1) channels in vivo. (Pubmed Central) - Apr 29, 2022
It was envisaged to synthesize [F]senicapoc ([F]1) since senicapoc (1) shows high affinity and excellent selectivity towards the K3.1 channels...Since [F]fluoride was detected in vivo after application of [F]28, an in vitro metabolism study was conducted. A potential degradation route of fluoroethoxy derivatives in vivo was found which in general should be taken into account when designing new PET tracers for different targets with a [F]fluoroethoxy moiety as well as when using the popular prosthetic group [F]fluoroethyl tosylate for the alkylation of phenols.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Enrollment open, Trial completion date, Trial primary completion date: Senicapoc in Alzheimer's Disease (clinicaltrials.gov) - Mar 24, 2022
P2, N=55, Recruiting,
These findings indicate that blocking K 3.1 channels is a potential treatment in ARDS-like disease. Not yet recruiting --> Recruiting | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Dec 2022 --> Dec 2024
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial completion date, Trial primary completion date: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Mar 16, 2022
P1/2, N=6, Recruiting,
Not yet recruiting --> Recruiting | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Dec 2022 --> Dec 2024 Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Apr 2022 --> Apr 2023
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: KCa3.1 in diabetic kidney disease. (Pubmed Central) - Feb 1, 2022
Based on its role in fibrosis, inflammation and mitochondrial dysfunction, pharmacological inhibition of KCa3.1 may offer a promising alternative for the treatment of DKD. Due to its safety profile in humans, the repurposing of senicapoc has the potential to expedite an urgently needed new drug in DKD.
- |||||||||| Esbriet (pirfenidone) / Shionogi, Roche
Journal: Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis. (Pubmed Central) - Oct 31, 2021
Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the K3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Preclinical, Journal: Increased cerebral endothelium-dependent vasodilation in rats in the post-cardiac arrest period. (Pubmed Central) - Oct 31, 2021
In cerebral arteries, bradykinin-induced vasodilation was inhibited in the presence of either calcium-activated K channel blockers (UCL1684 and senicapoc) or the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride (l-NAME), whereas the combination abolished bradykinin-induced vasodilation across groups...Cerebral vasodilation was comparable between the 2-h groups, but markedly enhanced in response to bradykinin, NS309 (an opener of small and intermediate calcium-activated K channels), and sodium nitroprusside 4 h after cardiac arrest...Our findings show enhanced cerebral endothelium-dependent vasodilation 4 hours after cardiac arrest mediated by potentiated endothelial-derived hyperpolarization and NO pathways. Altered cerebral endothelium-dependent vasodilation may contribute to disturbed cerebral perfusion after cardiac arrest.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: Co-staining of KCa3.1 channels in NSCLC cells with a small-molecule fluorescent probe and antibody-based indirect immunofluorescence. (Pubmed Central) - Sep 29, 2021
The novel fluorescently labeled small molecule imaging probes 1 and 2 were synthesized by connecting a dimethylpyrrole-based BODIPY dye with a derivative of the K 3.1 channel inhibitor senicapoc via linkers of different length...This observation was explained by docking studies showing that the antibody used for indirect immunofluorescence and the probes 1 and 2 label different channel populations. Whereas the antibody binds at the closed channel conformation, the probes 1 and 2 bind within the open channel.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase. (Pubmed Central) - Sep 22, 2021
The TEA-insensitive component was inhibited by senicapoc-a specific inhibitor of the Ca-activated KCa3.1 channel...The potassium currents and [Ca] increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Clinical, Journal: Mechanistic ion channel interactions in red cells of patients with Gárdos channelopathy. (Pubmed Central) - Sep 15, 2021
Assessing the RBC Ca2+ response by Fluo-4-based flow cytometry and by measuring the membrane potential using the Macey-Bennekou-Egée method, we provide data that support the concept of the KCa3.1/CaV2.1/Piezo1 interplay as a partial explanation for an increased number of high Ca2+ RBCs. With the pharmacological inhibition of KCa3.1 (TRAM34 and Senicapoc), CaV2.1 (ω-agatoxin TK), and Piezo1 (GsMTx-4), we could project the NS309 behavior of healthy RBCs to the RBCs of Gárdos channelopathy patients.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: Targeting K3.1 Channels in Cancer. (Pubmed Central) - Sep 3, 2021
The aim of this review is (i) to give an overview on the role of K3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using K3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to K3.1 channels in order to provide a deeper understanding of K3.1 channel pharmacology. Alltogether, K3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Review, Journal: Ca signalling in fibroblasts and the therapeutic potential of K 3.1 channel blockers in fibrotic diseases. (Pubmed Central) - Jun 22, 2021
The selective K 3.1 blocker senicapoc was well tolerated in human clinical trials for sickle cell disease, raising the possibility of rapid translation to the clinic for people suffering from pathological tissue fibrosis. This review is a comprehensive analysis of the data suggesting that targeting K 3.1 should be a high priority for human fibrotic disease.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Preclinical, Journal: Treatment with senicapoc in a porcine model of acute respiratory distress syndrome. (Pubmed Central) - Apr 22, 2021
In summary, senicapoc failed to improve the primary endpoint PaO/FiO ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Enrollment open: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Apr 14, 2021
P1/2, N=6, Recruiting,
These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS. Not yet recruiting --> Recruiting
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Journal: A validated UHPLC-MS/MS method for rapid determination of senicapoc in plasma samples. (Pubmed Central) - Mar 26, 2021
The relative intra-laboratory reproducibility standard deviations of the measured concentrations were 8% and 4% at concentrations of 0.1 ng/mL and 250 ng/mL, respectively. The trueness expressed as the relative bias of the test results was within ± 2% at concentrations of 1 ng/mL or higher.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
New P2 trial: Senicapoc in Alzheimer's Disease (clinicaltrials.gov) - Mar 17, 2021
P2, N=55, Not yet recruiting,
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Preclinical, Journal: Synthesis of novel small-molecule fluorescently labeled probes for the in vitro imaging of KCa3.1 channels. (Pubmed Central) - Mar 12, 2021
The punctate structure of the labeled channels could be observed in living cells as well. Molecular modeling studies showed binding of the senicapoc targeting component towards the binding site within the ion channel and orientation of the linker with the dye along the inner surface of the ion channel.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health, Thalomid (thalidomide) / Fujimoto, BMS
Journal: Role of thalidomide, senicapoc, and sodium butyrate in choroidal neovascularization. (Pubmed Central) - Feb 26, 2021
Thalidomide also reduced cobalt chloride induced increase of VEGFA mRNA in ARPE-19 (-33%) and protein in culture medium (-20%). Our results suggest that thalidomide may have more therapeutic potential than senicapoc or sodium butyrate for treatment of CNV or wet AMD.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial completion date, Trial primary completion date: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Feb 2, 2021
P1/2, N=6, Not yet recruiting,
Our results suggest that thalidomide may have more therapeutic potential than senicapoc or sodium butyrate for treatment of CNV or wet AMD. Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: Feb 2021 --> Mar 2022
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial initiation date: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Dec 9, 2020
P1/2, N=6, Not yet recruiting,
According to these results, SNEDDS formulations could be promising tools for the oral delivery of SEN. Initiation date: Oct 2020 --> Jan 2021
- |||||||||| Oxbryta (voxelotor) / Global Blood Therap
[VIRTUAL] Efficacy and Safety of Voxelotor in Sickle Cell Disease: A Systematic Review () - Nov 5, 2020 - Abstract #ASH2020ASH_4807;
Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc).
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
[VIRTUAL] Dehydrated Hereditary Stomatocytosis in a Multi-Generational American Family with a KCNN4 Gardos Channel Mutation () - Nov 5, 2020 - Abstract #ASH2020ASH_4757;
This disorder is likely much more prevalent than reported, due to the rarity of stomatocytes on peripheral blood smears, the omission of the KCNN4 gene from hemolytic panels offered by some reference laboratories, and variable clinical presentation. KCNN4 mutations should be investigated if other causes are not identified in patients with lifelong hemolytic anemia suspected of having a red cell membrane protein or cytoskeletal disorder.
- |||||||||| senicapoc (ICA-17043) / SpringWorks Therap, UC Davis Health
Trial initiation date: Senicapoc and Dehydrated Stomatocytosis (clinicaltrials.gov) - Aug 7, 2020
P1/2, N=6, Not yet recruiting,
KCNN4 mutations should be investigated if other causes are not identified in patients with lifelong hemolytic anemia suspected of having a red cell membrane protein or cytoskeletal disorder. Initiation date: Jul 2020 --> Oct 2020
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