Pathways

Ramucirumab serves as an antineoplastic agent and direct antagonist of VEGFR2 (vascular endothelial growth factor receptor 2), counteracting the binding of natural VEGF ligands secreted by solid tumors. This action inhibits angiogenesis and the enhancement of tumor blood supply, pivotal processes for cancer progression. It is a human monoclonal antibody (IgG1) designed against VEGFR2, a transmembrane tyrosine kinase receptor expressed on endothelial cells. By binding to VEGFR2, ramucirumab disrupts the binding of ligands (VEGF-A, VEGF-C, and VEGF-D), thereby impeding receptor phosphorylation and downstream cellular responses like proliferation, permeability, and migration of endothelial cells. Since VEGFR stimulation plays a crucial role in angiogenesis and cancer progression, ramucirumab's targeted interference is highly significant. Notably, it binds to a specific epitope on the extracellular domain of VEGFR-2, blocking all VEGF ligands from binding. Ramucirumab finds application in the treatment of advanced gastric or gastro-esophageal junction adenocarcinoma, metastatic non-small cell lung cancer with specific genomic mutations, metastatic colorectal cancer, and hepatocellular carcinoma, often in combination with other therapies.

Ranitidine is an anti-ulcer agent, that works through antagonizing the histamine H2 receptor. It is used to reduce abdominal pain, heartburn, acid indigestion and acid reflux. The pathway begins in the stomach, where ranitidine inhibits the histamine H2 receptor on the surface of the parietal cell. Now in the gastric endothelial cell, potassium-transporting ATPase units are inhibited by G-Protein signalling cascade through somatostatin receptor type 4, which is activated by somatostatin. At the same time, potassium-transporting ATPase is activated by the G-protein signalling cascade, through histamine H2 receptor which is inhibited by ranitidine, gastrin/cholecystokinin type B receptor, and muscarinic acetylcholine receptor M3 which are activated by histamine, gastrin and acetylcholine, respectively. The potassium transporting ATPase also converts water and ATP to a phosphate molecule and ADP. Alongside the transporters, potassium is brought into the cell. Carbonic anhydrase 1 uses water and carbon dioxide to create hydrogen carbonate and a hydrogen ion, which are both transported out of the endothelial cell, into the gastric lumen. A chloride ion is transported into the gastric endothelial cell through a chloride anion exchanger and is transported out of the cell through a chloride intracellular channel protein 2, back into the gastric lumen.

Ranitidine is an histamine H2 receptor antagonist used to treat stomach ulcers and Gastroesophageal Reflux Disease (GERD). After being taken orally, it is absorbed in the GI tract and travels through the blood to get to the stomach epithelium. Ranitidine binds reversibly to the histamine H2 receptor blocking histamine from binding instead. This blocks the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

Ranolazine is an anti-anginal drug used for the treatment of chronic angina. It can be found under the brand names Aspruzyo Sprinkle and Ranexa. Chronic angina is a common cardiovascular condition affecting millions worldwide and causes significant disability while interfering with daily activities. Ranolazine is a well-tolerated piperazine derivative used for the management of this condition, offering relief from uncomfortable and debilitating symptoms. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors. Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others. The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed. It has been shown to exert weak activity on L-type calcium channels. Some side effects of using ranolazine may include chest tightness, laboured breathing, and lightheadedness. Ranolazine is administered as an oral tablet.

Metabolites of Template3MB4 are predicted with biotransformer.

RAS signalling pathway is one of the main pathways to transduce intracellular signals in response to mitogens to controls cell growth, survival and anti-apoptotic programs. RAS proteins are GTP-binding proteins and must be bound to GTP to be active. Active RAS binds and activates effector enzymes that control cell proliferation, survival and other cell behaviours. RAS interacts directly with the catalytic subunit of PI3K to activate lipid kinases controlling the activity of downstream enzymes. Some of these kinases have anti-apoptotic activity, playing an important role in the survival signal of RAS. PI3K is also involved in the regulation of the actin cytoskeleton and transcription factor pathways. RAS also effects exchange factors causing inhibition of transcription factors from FoxO family, part of promoting cell cycle arrest and apoptosis. Normal function of these proteins require post-transcriptional modification. Pathway mutations in activation may result in human tumours.