- |||||||||| emricasan (IDN 6556) / Amerimmune
Journal: The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury. (Pubmed Central) - May 5, 2024
The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan...Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.
- |||||||||| Baynas (ramatroban) / Bayer, KARE Biosci, rimeporide (EMD 87580) / EspeRare, emricasan (IDN 6556) / Amerimmune
Journal, Adverse events: Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal. (Pubmed Central) - Apr 1, 2024
By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium-hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.
- |||||||||| Review, Journal: Biomaterials Functionalized with Inflammasome Inhibitors-Premises and Perspectives. (Pubmed Central) - Feb 23, 2024
Moreover, phytochemicals inhibit the inflammasomes by neutralizing reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents onto different nanomaterials could represent future research directions to facilitate multimodal and sequential treatment in oral pathologies.
- |||||||||| emricasan (IDN 6556) / Amerimmune
Retrospective data, Review, Journal: Emricasan for the treatment of liver cirrhosis: a meta-analysis of randomized controlled trials. (Pubmed Central) - Jan 19, 2024
Overall, compared with control group for liver cirrhosis, emricasan treatment had no substantial impact on MELD (SMD=-0.19; 95% CI=-0.44 to 0.06; P=0.14), INR (SMD=0.12; 95% CI=-0.13 to 0.37; P=0.36), total bilirubin (SMD=-0.27; 95% CI=-0.56 to 0.01; P=0.06), serum albumin (SMD=0; 95% CI=-0.25 to 0.25; P=1.00) or adverse events (OR=1.35; 95% CI=0.56 to 3.24; P=0.50). Emricasan treatment provided no benefit for the treatment of liver cirrhosis.
- |||||||||| emricasan (IDN 6556) / Amerimmune
Preclinical, Journal: Caspase cleavage of RIPK3 after Asp is dispensable for mouse embryogenesis. (Pubmed Central) - Jan 9, 2024
Ripk3 macrophages died at the same rate as wild-type (WT) macrophages in response to TNF plus cycloheximide, TNF plus emricasan, or infection with murine cytomegalovirus (MCMV) lacking M36 and M45 to inhibit caspase-8 and RIPK3 activation, respectively. We conclude that caspase cleavage of RIPK3 is dispensable for mouse development, and that cleavage of caspase-8 substrates, including RIPK1, is sufficient to prevent necroptosis.
- |||||||||| emricasan (IDN 6556) / Amerimmune
Preclinical, Journal, Monotherapy: An oral caspase inhibitor as monotherapy or with antibiotics eradicates MRSA skin infections in mice. (Pubmed Central) - Dec 18, 2023
Importantly, the efficacy of emricasan against S. aureus was not due to direct antibacterial activity. Collectively, pan-caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host-directed immunotherapy against MRSA skin infections in a preclinical mouse model.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Z-DNA BINDING PROTEIN 1 AGGRAVATED THE SEPSIS-INDUCED ACUTE KIDNEY INJURY VIA PANOPTOSIS (Focussed Oral Room 5) - May 4, 2023 - Abstract #ERAEDTA2023ERA_EDTA_836;
Collectively, pan-caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host-directed immunotherapy against MRSA skin infections in a preclinical mouse model. ZBP1 exacerbated SI-AKI via activating PANoptosis with the potencial PANoptosome of ZBP1, caspase 8, pglyrp1, and RIPK1.
- |||||||||| LCL161 / Novartis, emricasan (IDN 6556) / Histogen, Amerimmune
Preclinical, Journal: Celastrol inhibits necroptosis by attenuating the RIPK1/RIPK3/MLKL pathway and confers protection against acute pancreatitis in mice. (Pubmed Central) - Apr 4, 2023
Moreover, in a mouse model of acute pancreatitis that is associated with necroptosis, celastrol administration significantly reduced the severity of caerulein-induced acute pancreatitis accompanied by decreased phosphorylation of MLKL in pancreatic tissues. Collectively, celastrol can attenuate the activation of RIPK1/RIPK3/MLKL signaling likely by attenuating mtROS production, thereby inhibiting necroptosis and conferring protection against caerulein-induced pancreatitis in mice.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
The irreversible pan-caspase inhibitor emricasan is a potential host-directed immunotherapy against methicillin-resistant S. aureus (MRSA) skin infections in mice () - Mar 4, 2023 - Abstract #ISID2023ISID_1275;
When compared to placebo, all three groups, placebo plus doxycycline, emricasan plus doxycycline, and emricasan treated group, exhibited biological effect, with reduction of both the lesion size (*p=0.0277, ****p<0.0001, ****p<0.0001, respectively) and bacterial burden (***p=0.003, ****p<0.0001, ****p<0.0001, respectively). Collectively, pan-caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host-directed immunotherapy against MRSA skin infections in a preclinical mouse model.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences, emricasan (IDN 6556) / Histogen, Amerimmune
Journal: Primary cilia suppress Ripk3-mediated necroptosis. (Pubmed Central) - Dec 4, 2022
Cell death could be enhanced and shifted toward necroptosis by the caspase inhibitor emricasan, which could be blocked by inhibitors of Ripk1 and Ripk3...Moreover, loss of Nphp1, the most frequent cause of NPH, further increased susceptibility to necroptosis in non-ciliated epithelial cells, suggesting that necroptosis might contribute to the pathogenesis of the disease. Together, these data provide a link between cilia-related signaling and cell death responses and shed new light on the disease pathogenesis of NPH-related ciliopathies.
- |||||||||| DIACC2010 / Diaccurate
DIACC2010, Sole-in-Class Selective Inhibitor of Kinesin KIF20A, Has Potent Preclinical Efficacy in Acute Myeloid Leukemia (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4863;
In the same experimental conditions, cytarabine (CYTA) had median IC50 of 207 nM (range 4-1580 nM)...Nevertheless, caspase inhibitors ZVAD-fmk and Emricasan partially rescued DIACC2010 cell death, although these inhibitors significantly rescued caspase activation induced by Venetoclax, a BCL-2 inhibitor triggering intrinsic apoptosis commonly used in AML treatment... Altogether, these results confirm the relevance of KIF20A-directed therapeutic approaches and support the development of DIACC2010 for the treatment of AML.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Journal: Gout-associated monosodium urate crystal-induced necrosis is independent of NLRP3 activity but can be suppressed by combined inhibitors for multiple signaling pathways. (Pubmed Central) - May 6, 2022
Moreover, a triple combination of GSK'872, GW806742X, and IDN-6556 (pan-caspase inhibitor) displayed enhanced inhibition of the necrosis, which was further fortified by the addition of MCC950 (NLRP3 inhibitor), suggesting that multiple cell death pathways might have been triggered by MSU crystals...Besides, baicalin gavage significantly ameliorated MSU crystal-induced peritonitis in mice. Altogether, our data indicate that MSU crystals induce NLRP3-independent necrosis, which can be inhibited by combined inhibitors for multiple signaling pathways, highlighting a new avenue for the treatment of gouty arthritis.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Journal: Reprogramming monocyte-derived macrophages through caspase inhibition. (Pubmed Central) - Apr 9, 2022
Interestingly, caspase inhibition also triggered the reprogramming of monocyte-derived cells evidenced by RNA sequencing. Taken together, our findings position Emricasan as a potential alternative to current therapies for reprogramming macrophages in diseases driven by monocyte-derived macrophages.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Review, Journal: The impact of emricasan on chronic liver diseases: current data. (Pubmed Central) - Apr 1, 2022
Even though, this intrahepatic drug effect confirmed in human clinical trials, no clear linkage was emerged with portal hypertension, liver function or liver histology in both non-cirrhotic and cirrhotic patients except from a subgroup of patients with high MELD score (> 15) or severe HVPG (> 16 mmHg). As emricasan treatment appeared safe and well-tolerated, irrespective the severity of liver disease, more studies are required to clarify better these subgroups of patients who may benefit most from this drug.
- |||||||||| tolinapant (ASTX660) / Otsuka
Clinical, Journal: Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer. (Pubmed Central) - Feb 11, 2022
Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8-proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Clinical, Journal: Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. (Pubmed Central) - Jan 21, 2022
P2
Emricasan was safe but ineffective in treatment of decompensated NASH cirrhosis with regard to MELD-Na score improvement, reducing new decompensation events, improving liver function or mortality. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Journal: Vitamin B6 Alleviates Lipopolysaccharide-induced Myocardial Injury by Ferroptosis and Apoptosis Regulation. (Pubmed Central) - Jan 11, 2022
To confirm that VitB6 could inhibit LPS-induced ferroptosis and apoptosis, we pretreated mice with ferrostatin-1 (Fer-1) and emricasan that efficiently mimicked VitB6 pharmacological effects...It mediated the expression of Nrf2, transcription factor NF-E2-related factor 2, which promoted the expression of antioxidant enzymes and restrained LPS-induced ferroptosis and apoptosis. Overall, our results indicated that VitB6 can be used on novel therapies to relieve LPS-induced myocardial injury.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Journal: Caspases and therapeutic potential of caspase inhibitors in moderate-severe SARS CoV2 infection and long COVID. (Pubmed Central) - Jan 5, 2022
Ourpreliminary resultssuggestan exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes.Further clinical correlations of caspase expression in differentstages of COVID-19 will be needed. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorateor prevent severe COVID-19.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Clinical, Journal: The importance of clinically relevant background therapy in cardioprotective studies. (Pubmed Central) - Oct 22, 2021
However, using a caspase inhibitor, which acts via a different mechanistic pathway to RIC, we were able to demonstrate additional protection (20.6 ± 3.3%). This concept provides initial evidence to develop models which can be used to evaluate future animal-to-clinical translation in cardioprotective studies.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Clinical, Journal: A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. (Pubmed Central) - Oct 8, 2021
P2
Emricasan treatment did not improve liver histology in subjects with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum ALT in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning.
- |||||||||| Clinical, Review, Journal: Efficacy and safety of drugs for nonalcoholic steatohepatitis. (Pubmed Central) - Sep 19, 2021
Vitamin E has been recommended for patients with NASH without type 2 diabetes mellitus (T2DM), whereas a combination of pioglitazone and vitamin E is recommended for patients with both NASH and T2DM...Some of the drugs are at phase III clinical trials, including obeticholic acid (OCA), Elafibranor, Cenicriviroc, Selonsertib, Resmetirom, Emricasan and Aramchol...Especially, due to the interim positive effect for the improvement of liver fibrosis, OCA has been filling to FDA and is waiting for the final approval for the treatment of NASH. Therefore, it is urgent to review the efficacy and safety of drugs for NASH in current clinical trials.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Journal: A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells. (Pubmed Central) - Jul 29, 2021
CEPT provided strong improvements for several key applications in stem-cell research, including routine cell passaging, cryopreservation of pluripotent and differentiated cells, embryoid body (EB) and organoid formation, single-cell cloning, and genome editing. Thus, CEPT represents a unique poly-pharmacological strategy for comprehensive cytoprotection, providing a rationale for efficient and safe utilization of hPSCs.
- |||||||||| emricasan (IDN 6556) / Histogen, Amerimmune
Clinical, Journal: Efficacy and Safety of Emricasan in Liver Cirrhosis and/or Fibrosis. (Pubmed Central) - Jun 22, 2021
Treatment with emricasan is more effective in improving liver function and apoptosis parameters compared to placebo, with a well-tolerated safety profile. However, due to the poor quality of the analyzed studies, the small number of trials and patients, and the short follow-up periods, more robust trials are still warranted.
- |||||||||| birinapant (TL 32711) / Medivir, emricasan (IDN 6556) / Histogen, Amerimmune
Journal: Caspase 8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic induced necroptosis. (Pubmed Central) - May 25, 2021
Although an in vitro screen revealed that low RIP3 levels render many HNSCC cell lines resistant to necroptosis, patient tumors maintain RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.
- |||||||||| Review, Journal: Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention. (Pubmed Central) - May 15, 2021
While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.
- |||||||||| QPI-1007 / Quark, emricasan (IDN 6556) / Conatus, Amerimmune
Clinical, Journal: Caspase inhibition: From cellular biology and thanatology to potential clinical agents (Pubmed Central) - Jan 26, 2021
The Pan-caspase inhibitor emricasan reached clinical phase III and was proven to be safe but failed to demonstrate efficacy against NASH. Contrary to initial assumptions, selective Caspase-3 inhibitors have not reached the clinical level, while QPI-1007, a siRNA directed against Caspase-2, is currently undergoing a multicentric phase III clinical study for the treatment of ischemic optic neuropathies.
- |||||||||| Biomarker, Clinical, Journal, Monotherapy: Biomarker Profile for Prediction of Response to SMAC Mimetic Monotherapy in Pediatric Precursor B-Cell Acute Lymphoblastic Leukemia. (Pubmed Central) - Jan 9, 2021
Here, we analyzed the intrinsic activity of two monovalent (AT406 and LCL161) and two bivalent (Birinapant and BV6) SMs on unselected patient-derived pediatric precursor B-cell acute lymphoblastic leukemia (BCP-ALL) identifying a subset of patient samples to be particularly sensitive to SM-induced cell death...Interestingly, samples with intermediate or low sensitivity to SMs were sensitized to SM-induced cell death by inhibition of caspases using zVAD.fmk or Emricasan, a pan-caspase inhibitor in clinical trials...Functional testing revealed that this set of genes identified samples with high sensitivity to SM treatment. In summary, our data suggest using this gene signature as biomarker predicting response to SM treatment and point to the development of new combinatorial treatments consisting of SMs and pan-caspase inhibitors for a successful clinical implementation of SMs in treatment of BCP-ALL.
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