Last update 01 Nov 2024

CRAF x Cytokines

Last update 01 Nov 2024

Basic Info

Related Targets

CRAFCytokines

Drugs associated with CRAF x Cytokines

Semapimod Mesylate

Target

CRAF x Cytokines

Mechanism

CRAF inhibitors [+2]

Active Org.-

Originator Org.

Ferring BV

Active Indication-

Inactive Indication

Chemotherapy-induced damage [+5]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with CRAF x Cytokines

NCT00950105 / CompletedPhase 1

A Phase 1, Single Center, Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetic Profiles of Oral CPSI-2364 in Healthy Subjects

This study will be conducted in healthy male or female subjects using a double-blind, randomized, placebo-controlled, single-dose design. Up to 30 subjects will be enrolled; 3 healthy subjects in Cohorts 1 and 2 (2 active, 1 placebo) and 8 healthy subjects in Cohorts 3 to 5 (6 active, 2 placebo). The following CPSI-2364 doses are proposed: 1 mg, 10 mg, 30 mg, 90 mg, and 270 mg.Safety will be evaluated throughout the study and include physical examinations, vital signs assessments, 12-lead electrocardiograms (ECGs), routine clinical laboratory tests (including blood chemistry, hematology, coagulation, and urinalysis), and adverse event (AE) assessments. Vital sign assessments and 12-lead ECGs will be performed repeatedly over the 24-hour observation period. Venous blood samples will be taken at specified intervals and tested for the presence of CPSI-2364.

Start Date01 Jul 2009

Sponsor / Collaborator

Ferring Pharmaceuticals A/S

NCT00741910 / CompletedPhase 2

Extension Study of CNI-1493 for Treatment of Moderate to Severe Crohn's Disease

Study CNI-1493-CD06 is an open, single-arm extension studies to CD03 and CD05. CDAI is the only efficacy measure assessed in this study. The safety of multiple courses of semapimod is to be determined by the incidence of clinical and laboratory adverse events.

Start Date01 Jul 2003

Sponsor / Collaborator

Ferring Pharmaceuticals A/S

NCT00740103 / CompletedPhase 2

Long-term Study of Semapimod (CNI-1493) for Treatment of Moderate to Severe Crohn's Disease With Reference to Study CNI-1493-CD-04, 1 or 3 Days' Treatment vs. Placebo

CNI-1493-CD05 is an open-label extension study of CNI-1493-CD04. In the CD05 study, patients are eligible for up to 5 courses of semapimod 60 mg IV x 3 days every 6 - 8 weeks. Primary objective is assessment of the efficacy of cumulative doses of semapimod measured by decrease in Crohn's Disease Activity Index (CDAI).

Start Date01 Dec 2002

Sponsor / Collaborator

Ferring Pharmaceuticals A/S

100 Clinical Results associated with CRAF x Cytokines

100 Translational Medicine associated with CRAF x Cytokines

0 Patents (Medical) associated with CRAF x Cytokines

692

Literatures (Medical) associated with CRAF x Cytokines

31 Dec 2024·Annals of Medicine

Substance basis and pharmacological mechanism of heat-clearing herbs in the treatment of ischaemic encephalopathy: a systematic review and network pharmacology

Review

Author: Zhao, Andong ; Wang, Chuan ; Zhang, Jiahao ; Liu, Jiping ; Sun, Qianqian ; Zhou, Xuewei ; Hu, Tian ; Wang, Bin

BACKGROUND AND OBJECTIVEIschaemic encephalopathy is a common cerebrovascular disease caused by insufficient blood supply to the cerebral vessels. The ischaemic encephalopathy is closely associated with the development of many chronic diseases such as obesity, hypertension and diabetes. Neurotrophic therapy has become the main therapeutic strategy for ischaemic encephalopathy. However, neurotrophic drugs only slightly recover the neurological function of patients, and their long-term efficacy is uncertain. Previous reports revealed that the active ingredients of natural medicines play important roles in the treatment of cerebral ischemia. In this study, we reviewed clearing herbs with anti-ischaemic encephalopathy functions using the data from quantitative statistical and network pharmacological exploration methods. We also discussed the different bioactive components and pharmacological effects of these herbs.METHODSFirst, we collected Chinese herbal prescriptions against ischaemic encephalopathy in four databases. Then, we statistically analysed the frequency of application of heat-clearing herbs to obtain the commonly used heat-clearing herbs against ischaemic encephalopathy, and classified them according to their efficacy according to the statistical results, to summarize the mechanism of anti-ischaemic effects of different bioactive components; Second, the network database was used to obtain the above components of heat-clearing Chinese medicines and their corresponding targets of action, disease targets of ischaemic stroke; Venny 2.1.0 was used to obtain component-disease target intersections; Cytoscape was used to construct the 'Drug-Active Ingredient-Target Network Graph '; DAVID was used for GO and KEGG enrichment analysis.RESULTSLiterature and database screening involved 149 prescriptions, with a total of 269 flavours of Chinese medicines and 20 flavours of single-flavour heat-clearing Chinese medicines; The top nine in terms of frequency of use were Radix Paeoniae Rubra、Rehmanniae Radix Praeparata、Figwort Root、Cortex Moutan、Scutellariae Radix、Coptidis Rhizoma、Gardeniae Fructus、Cassiae Semen、Lonicerae Japonicae Flos. The common components obtained from network pharmacology were beta-sitosterol, quercetin, and stigmasterol, which mainly act on key targets such as RELA, AKT1, JUN, PRKACA, PTGS2, RAF1 and CHUK; and their active ingredients are mainly involved in signalling pathways such as Calcium, PI3K-Ak, MAPK, cAMP, IL-17, HIF-1, TNF, T-cell receptor, NF-kappa B and JAK-STAT.CONCLUSIONSHeat-clearing herbs are useful and promising for the protection against and prevention of ischemic encephalopathy. The results of the network pharmacological studies are similar to the mechanisms of anti-ischemic encephalopathy of the active ingredients of the purgative herbs we have listed; Thin either directly protects cerebrovascular tissues by improving vascular permeability and reducing the area of infarcted tissues, or produces protective effects through molecular signaling pathways. It can be seen that the components of heat-clearing Chinese medicines can exert cerebroprotective effects through multiple pathways, which provides us with a reference for further development and study of heat-clearing Chinese medicines in the treatment of ischemic cerebrovascular diseases.

01 Sep 2024·Neurochemical Research

Vitamin D Relieves Epilepsy Symptoms and Neuroinflammation in Juvenile Mice by Activating the mTOR Signaling Pathway via RAF1: Insights from Network Pharmacology and Molecular Docking Studies

Article

Author: Chen, Xiuling ; Xiang, Wei ; Lu, Tiantian ; Yang, Xiaogui ; Zhang, Qin ; Shang, Kun

Epilepsy is a common neurological disorder, and the exploration of potential therapeutic drugs for its treatment is still ongoing. Vitamin D has emerged as a promising treatment due to its potential neuroprotective effects and anti-epileptic properties. This study aimed to investigate the effects of vitamin D on epilepsy and neuroinflammation in juvenile mice using network pharmacology and molecular docking, with a focus on the mammalian target of rapamycin (mTOR) signaling pathway. Experimental mouse models of epilepsy were established through intraperitoneal injection of pilocarpine, and in vitro injury models of hippocampal neurons were induced by glutamate (Glu) stimulation. The anti-epileptic effects of vitamin D were evaluated both in vivo and in vitro. Network pharmacology and molecular docking analysis were used to identify potential targets and regulatory pathways of vitamin D in epilepsy. The involvement of the mTOR signaling pathway in the regulation of mouse epilepsy by vitamin D was validated using rapamycin (RAPA). The levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Gene and protein expressions were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining was used to analyze the apoptosis of hippocampal neurons. In in vivo experiments, vitamin D reduced the Racine scores of epileptic mice, prolonged the latency of epilepsy, and inhibited the production of TNF-α, IL-1β, and IL-6 in the hippocampus. Furthermore, network pharmacology analysis identified RAF1 as a potential target of vitamin D in epilepsy, which was further confirmed by molecular docking analysis. Additionally, the mTOR signaling pathway was found to be involved in the regulation of mouse epilepsy by vitamin D. In in vitro experiments, Glu stimulation upregulated the expressions of RAF1 and LC3II/LC3I, inhibited mTOR phosphorylation, and induced neuronal apoptosis. Mechanistically, vitamin D activated the mTOR signaling pathway and alleviated mouse epilepsy via RAF1, while the use of the pathway inhibitor RAPA reversed this effect. Vitamin D alleviated epilepsy symptoms and neuroinflammation in juvenile mice by activating the mTOR signaling pathway via RAF1. These findings provided new insights into the molecular mechanisms underlying the anti-epileptic effects of vitamin D and further supported its use as an adjunctive therapy for existing anti-epileptic drugs.

01 Jun 2024·Regenerative Therapy

Cytokines secreted from bone marrow-derived mesenchymal stem cells promote apoptosis of CD34+ leukemic stem cells as anti-cancer therapy

Article

Author: Fathi, Ezzatollah ; Valipour, Behnaz ; Vandghanooni, Somayeh ; Farahzadi, Raheleh

ObjectiveThe effect of mesenchymal stem cells (MSCs) on the immortal characteristics of malignant cells, particularly hematologic cancer cells, remains a topic of debate, with the underlying mechanisms still requiring further elucidation. We explored the in vitro effect of the bone marrow-derived MSCs (BM-MSCs) on CD34⁺ leukemic stem cells (LSCs) enriched from the KG1-a cell line by assessing apoptosis, measuring cytokine levels, and examining TERT protein expression. Additionally, the potential signaling pathways implicated in this process, such as P53, PTEN, NF-κB, ERK1/2, Raf-1, and H-RAS, were also investigated.MethodsCD34⁺ LSCs were enriched from the KG1-a cell line with the magnetic activated cell sorting (MACS) method. Two cell populations (BM-MSCs and CD34⁺ LSCs) were co-cultured on trans well plates for seven days. Next, CD34⁺ LSCs were collected and subjected to Annexin V/PI assay, cytokine measurement, and western blotting.ResultsBM-MSCs caused a significant increase in early and late apoptosis in the CD34⁺LSCs. The significant presence of interleukin (IL)-2 and IL-4 was evident in the co-cultured media. In addition, BM-MSCs significantly increased the protein expression of P53, PTEN, NF-κB, and significantly decreased p-ERK1/2, Raf-1, H-RAS, and TERT.ConclusionThe mentioned effects of IL-2 and IL-4 cytokines released from BM-MSCs on CD34⁺ LSCs as therapeutic agents were applied by the components of P53, PTEN, NF-κB, p-ERK1/2, Raf-1, and H-RAS signaling pathways.

News (Medical) associated with CRAF x Cytokines

27 May 2022

·www.biospace.com

Clinical Catch-Up: 3's the Charm for Pfizer-BioNTech Vaccine in Kids & More

As Memorial Day officially kicks off the summer season, there are plenty of clinical trial highlights. Here’s a look. COVID-19-Related Pfizer released toplined data from its Phase II/III trial of the Pfizer-BioNTech COVID-19 vaccine in children ages six months to five years. The data support the use of a three-dose regimen. Ocugen reported the FDA had lifted a second clinical hold on its studies of Covaxin, a COVID-19 vaccine. The hold was placed on a Phase II/III trial over concerns about the company’s developmental partner Bharat Biotech International Limited’s manufacturing facility. Edesa Biotech announced it had initiated enrollment for a second cohort of patients for the Phase III portion of a Phase II/III trial of EB05 for COVID-19-induced Acute Respiratory Distress Syndrome (ARDS). The drug is a monoclonal antibody. Codagenix dosed the first patient in a Phase I trial of CoviLiv as a booster in healthy adults after previous vaccination with approved COVID-19 vaccines. CoviLiv is an intranasal, live-attenuated virus vaccine. Moleculin Biotech initiated dosing in its Phase Ia trial of WP1122. The drug is a metabolism/glycosylation inhibitor being developed to treat COVID-19. Non-COVID-19-Related Armata Pharmaceuticals reported that it had dosed the first patient in its Phase Ib/IIa trial of AP-SA02 for adults with bacteremia from Staphylococcus aureus infections. In June 2020, the company was awarded $15 million from the U.S. Department of Defense through the Medical Technology Enterprise Consortium (MTEC) managed by the Naval Medical Research Center with funding from the Defense Health Agency and Joint Warfighter Medical Research Program, to evaluate AP-SA02 as an adjunct to best available antibiotic treatment. Alnylam Pharmaceuticals reported 18-month results from a Phase III Helios-A trial of vutrisiran in transthyretin-mediated hereditary (hATTR) amyloidosis. Vutrisiran targets and silences the mRNA linked to the production of TTR proteins. The company also announced new positive results from the Phase III ILLUMINATE-C trial of lumasiran for advanced primary hyperoxaluria type 1 (PH1). The new results were a six-month primary analysis period of the ILLUMINATE-C trial of lumasiran. Lumasiran, marketed as Oxlumo and indicated for primary hyperoxaluria type 1, is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1), the gene encoding glycolate oxidase (GO). The company previously reported that lumasiran caused substantial reductions in plasma oxalate (POx) at six months. Regeneron Pharmaceuticals reported positive data from its Phase III trial of Evkeeza for homozygous familial hypercholesterolemia (HoFH). Evekeeza (evinacumab) is a fully human monoclonal antibody against ANGPTL3. Seres Therapeutics reported positive data from the Phase III ECOSPOR trial of SER-109 for the prevention of recurrent C. difficile infection. SER-109 is an oral microbiome therapeutic containing Firmicutes spores, typically found in healthy microbiomes. Vera Therapeutics announced new data from its Phase II trial of atacicept for systemic lupus erythematosus. Atacicept is a recombinant fusion protein. Day One Biopharmaceuticals dosed the first patients in sub-study 2 of FIRELIGHT-1, a Phase Ib/II trial of tovorafenib in combination with pimasertib in adolescent and adult patients with recurrent, progressive, or refractory solid tumors with MAPK pathway aberrations. The drug is an oral, brain-penetrant, highly selective type II pan-RAF kinase inhibitor. Pimasertib is an oral, highly selective small-molecule inhibitor of mitogen-activated protein kinases 1 and 2 (MEK-1/-2). Albireo presented analysis of its pivotal PEDFIC 1 and PEDFIC 2 studies of Bylavy for progressive familial intrahepatic cholestasis (PFIC). Bylvay is a potent, non-systemic once daily ileal bile acid transport inhibitor approved in the U.S. for pruritus in patients three months of age and older in all types of PFIC. Anokion announced positive results from the Phase I ACeD trial of KAN-101 for celiac disease. KAN-101 is designed to induce tolerance to gliadin, a core component of gluten. Vectorious Medical Technologies announced the results of Vector-HF I, a first-in-man study of its V-LAP wireless system for left atrial pressure management of heart failure. The V-LAP system in an implanted heart sensor. Janssen, a Johnson & Johnson company, published findings from the Phase III COMPASS long-term open-label extension study of Xarelto (rivaroxaban) and Xarelto in combination with acetylsalicylic acid (aspirin). The studies supported the role of dual pathway inhibition with Xarelto and aspirin in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD). The company also presented data from the Phase II Galaxi 1 trial of Tremfya (guselkumab) in moderately to severely active Crohn’s disease. The data demonstrated that patients who were intolerant of or had poor responses to conventional therapies achieved highly clinical biomarker response levels of 47.5% to 66.7%. Seagen announced positive topline results from the pivotal Phase II MOUNTAINEER trial of Tukysa (tucatinib) in combination with trastuzumab in patients with previously treated HER2-positive metastatic colorectal cancer. Tukysa is an oral TKI inhibitor. Stealth Biotherapeutics announced new data from the Phase II Reclaim-2 trial of elamipretide in geographic atrophy secondary to dry age-related macular degeneration. Elamipretide is designed to ameliorate mitochondrial-based diseases of the eye. Ascendis Pharma announced that results from Visen Pharmaceuticals’ Phase III trial of TransCon hGH in children with growth hormone deficiency in China demonstrated results consistent with Ascendis’ Phase III trial. The drug is already approved in U.S. and EU for pediatric GHD. Recce Pharmaceuticals announced that in cohort five of a Phase I trial, R327 demonstrated a good safety and tolerability pro 10 healthy male subjects. The drug, RECCE 327 is an IV and topical therapy being developed for serious and potentially life-threatening infections from Gram-positive and Gram-negative bacteria. Pfizer presented detailed results from two pivotal studies that make up the Elevate UC Phase III program of etrasimod for moderately-to-severely active ulcerative colitis (UC). The drug is a once-daily, oral, selective sphingosine 1-phosphate (S1P) receptor modulator. Both studies hit all primary and key secondary endpoints. SpringWorks Therapeutics announced positive topline results from the DeFi Phase III trial of nirogacestat in adults with progressing desmoid tumors. The drug is an oral gamma-secretase inhibitor. Eli Lilly shared results from its Phase III Lucent-2 trial of mirikizumab for ulcerative colitis. Patients who responded to the drug at 12 weeks achieved and maintained statistically superior and clinically meaningful improvements at one year compared to placebo across all primary endpoints of clinical remission and all key secondary endpoints. Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 subunit of interleukin 23. Imugene and City of Hope dosed the first patient in a Phase I trial of CF33-hNIS (Vaxinia) for metastatic or advanced tumors. The drug is a genetically altered oncolytic virus programmed to infiltrate cancer cells and cause them to burst. Alpine Immune reported the FDA had removed a partial clinical hold on its NEON-2 trial of davoceticept with Merck’s anti-PD-1 checkpoint inhibitor Keytruda (pembrolizumab) in adults with advanced malignancies. Davoceticept is a first-in-class conditional CD28 costimulator and dual checkpoint inhibitor. Luxa Biotechnology announced the first patient was transplanted with RPESC-RPE-4W for dry age-related macular degeneration in its Phase I/IIa trial. The therapy is a cell product derived from the retinal pigment epithelium stem cell (RPESC) that is present in the adult human retina. Aerie Pharmaceuticals dosed the first participant in the Phase III Comet-2 study of AR-15512 ophthalmic solution for dry eye disease. AR-15512 is a first-in-class TRPM8 agonist. Cingulate completed enrollment in its formulation study of CTx-2103 for the management of anxiety-related disorders. Results from the trial are expected in July 2022. CTx-2103 contains the active pharmaceutical ingredient buspirone hydrochloride, a non-benzodiazepine medication. Pharmazz announced positive topline data from its Phase III trial of sovateltide for acute ischemic stroke. The data at 90 days demonstrated mRS (median score reduction) had a significantly greater number of patients with an improvement of 2 or more points on mRS. It produced a statistically significant and clinically meaningful improvement in neurological outcomes in patients 90 days post-treatment. Endeavor BioMedicines dosed the first patient in an open-label Phase II trial of ENV-101 (taladegib) in patients with advanced solid tumors harboring Patched-1 loss of function mutations. ENV-101 is a Hedgehog signaling inhibitor. Oncotelic Therapeutics reported the FDA had approved its launch of a Phase II trial of OT-101 with Merck’s checkpoint inhibitor Keytruda in metastatic plural mesothelioma. OT-101 is a TGF-beta inhibitor. Crinetics Pharmaceuticals announced positive results from the multiple-ascending dose (MAD) portion of a Phase I trial of CRN04894 for Cushing’s disease. The drug is a first-in-class, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist. CytomX Therapeutics dosed the first patient in a Phase I trial of CX-904. The drug is a conditionally activated T-cell-engaging bispecific designed to target EGFR on cancer cells and the CD3 receptor on T-cells within the tumor microenvironment. SciSparc received Ethics Committee approval in Germany and Israel to run a Phase IIb trial of SCI-110 in patients with Tourette syndrome. The drug is based on cannabinoid pharmaceuticals. SELLAS Life Sciences Group announced topline data from its Phase I/II trial of galinpepimut-S for WT1(+) r/r platinum-resistant advanced metastatic ovarian cancer. The drug is a Wilms Tumor-1 (WT1)-targeting peptide immunotherapeutic. It is being evaluated with Merck’s anti-PD-1 drug Keytruda. Laekna Therapeutics dosed the first patients in a Phase Ib/III trial of afuresertib in combination with fulvestrant in HR+/HER2- breast cancer patients who failed after one or two lines of CDK4/6 inhibitors, endocrine, or chemotherapy treatments. Afuresertib in an AKT kinase inhibitor. Cynata Therapeutics received the green light from the FDA for a Phase II trial of CYP-001 in acute graft versus host disease. The drug is based on its stem cell platform technology, Cymerus. Yingli Pharma US dosed the first patient in its Phase I study of YL-13027. The drug is a potent and selective TGF beta receptor 1 inhibitor being developed for advanced solid tumors. Scioto Biosciences announced topline results from a Phase Ib trial of SB-121 in patients with an autism spectrum disorder. The drug is based on a novel microbiome delivery platform, Activated Bacterial Therapeutics (ABT), which delivers best-in-class, live therapeutic bacteria to the gut. The therapeutic was well tolerated. Biomind Labs received approval in Argentina to run a third Phase II trial of BMND08 for depression and anxiety in Alzheimer’s disease patients. The drug is a 5-Methoxy-N,N-dimethyltryptamine. Q32 Bio dosed the first patient in its Phase I trial of ADX-097 for complement disorders. The drug is a first-in-class fusion protein that inhibits complement activation. InnoCare Pharma received approval in China to run a Phase II trial of tafasitamab with lenalidomide for r/r diffuse large B-cell lymphoma patients not eligible for autologous stem cell transplantation. Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. Genentech, a Roche company, announced new data from its glofitamab for r/r diffuse large B-cell lymphoma. The drug is a CD20XCD3 T-cell engaging bispecific antibody. After treatment, 34.9% achieved a complete response, with half achieving an overall response. Adicet Bio announced positive preliminary data from its r/r B-cell NHL therapeutic ADI-001. The drug is a form of CAR T-cell therapy. Of six patients that could be evaluated, 67% had an OR or a CR. Bristol Myers Squib reported positive Phase II data from its study of Breyanzi (lisocabtagene maraleucel) for r/r large B-cell lymphoma after first-line therapy who were not deemed candidates for high-dose chemotherapy or hematopoietic stem cell transplant. Breyanzi is a form of CAR-T therapy. AstraZeneca announced the first patients had been dosed in the IRIS Phase III trial of Saphnelo (anifrolumab) in lupus nephritis. The drug has been approved for adults with moderate to severe systemic lupus erythematosus who are receiving standard care. Purple Biotech announced positive interim safety and efficacy data from the Phase I trial of NT219 in adults with advanced solid tumors. The drug is a first-in-class small molecule, a director inhibitor of Insulin Receptor Substrates ½ and STAT3.

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