Medicilon

Medicilon is an integrated contract research organization (CRO), providing comprehensive one-stop R&D services for pharmaceutical enterprises and scientific research institutions around the world. In the past 20 years, the development of Medicilon witnessed the global advancement of the pharmaceutical industry. On this special occasion of Medicilon’s 20th anniversary, we launch a new official promo. Medicilon is grateful for the love and support from all of you in pharmaceutical industry. Hope that we can work together for the next 20 years. Learn more: https://www.medicilon.com/

Throughout ages man has used many different remedies for pain relief. However, there are still some pain symptoms can’t be effectively alleviated. Because of different degrees of analgesic drug adverse reactions or efficacy intensity and duration is not ideal, the prevention and treatment of pain is still not up to the ideal degree. Various analgesics with different mechanisms of action and different types of analgesia need to be evaluated by corresponding animal models before clinical trials. When animals experience pain during an experimental protocol, a cascade of physiological, hormonal, biochemical, and behavioral alterations is triggered that’s simile the same way of human reaction. Therefore, we can choose the corresponding pain animal model to evaluate the new analgesic drugs. Animal models of pain are designed to mimic distinct clinical diseases to better evaluate underlying mechanisms and potential treatments. Neural System Disease Models Our Pharmacodynamics Department can deliver multiple nervous system models based on anti-depressants, anti-Alzheimer's drugs, sedative-hypnotic and anti-anxiety drugs, analgesics, anti-convulsants, anti-Parkinson's drugs, and anti-schizophrenia drugs. Those models can effectively evaluate innovative drugs at the molecular and cellular level, as well as ex vivo, and in vivo. The Department's advanced Cognition Wall Discrimination learning ensures uninterrupted tracking to determine changes in memory function in double transgenic mice during early-stage Alzheimer's disease and eliminates the disadvantages of the Morris water maze (MWM) in stress interference and short-time tests. https://www.medicilon.com/services/neurological-disorders-models/

The signal transducer and activator of transcription (STAT) is a family of intracellular cytoplasmic transcription factors involved in many biological functions in mammalian signal transduction. Among them, STAT3 is involved in cell proliferation, differentiation, apoptosis, and inflammatory responses, and also STAT3-related signaling pathways are aberrant over-activated in many types of cancer and are strongly associated with poor patient prognosis. https://www.medicilon.com/videos/stat3-introduction/ Excessive activation of STAT3 within tumor cells and other cells in the tumor microenvironment (TME) mediates a series of extracellular signals that enhances the immune inflammatory response in the TME, driving tumor cell proliferation, invasion, and metastasis, while strongly suppressing the anti-tumor immune response and creating an immunosuppressive microenvironment. Studies have indicated that persistently activated STAT3 is indispensable for various cancers including breast cancer and colorectal cancer, which makes it an ideal drug target. Medicilon provides STAT3 drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services.

Targeting KRAS is a desirable strategy because of the high prevalence of KRAS mutations and its importance in initiating and sustaining tumor growth. KRAS is the most commonly mutated member of the RAS family. KRAS mutations are seen in a variety of malignancies at different rates. Its incidence is highest in pancreatic cancers followed by colorectal cancer, NSCLC and cholangiocarcinoma. The profile of KRAS mutations differs significantly among diverse cancer types. 98% of KRAS mutations are found at G12, G13, or Q61. https://www.medicilon.com/platform/kras/ KRAS mutations occur in many cancers with different mutation frequencies, but there is also a large variation in mutation subtypes. The response to KRAS G12C inhibitors in patients is different, implicating the existence of resistance. Exploration of resistance should be conducted to identify biomarkers that indicate the appropriate population and tumor type in the clinical trial.

After decades of efforts, scientists have made progress into targeting KRAS mutations in several malignancies. In 1967, Ha-Ras and Ki-Ras retroviral transforming genes were discovered. Their human counterparts, HRAS and KRAS, were discovered in 1982. The relationship between KRAS and lung cancer was described in 1984, KRAS mutation in lung cancer has progressed. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. In 2021, covalent inhibitors that block mutant KRAS G12C were successfully developed. In May 2021, the US FDA granted accelerated approval to Sotorasib for the treatment of adults with advanced NSCLC with a KRAS G12C mutation. Sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Lung adenocarcinoma often occurs in the distal gas exchange areas of the lung and is characterized by tumor cells with AT2 cytologic and molecular characteristics. Multiple studies have pointed out that AT2 cells are the key origin cells of LuAd. The stem cell activity of AT2 is selectively induced by epidermal growth factor receptor ligand (EGFR) and oncogenic KRAS (G12D) in vivo. KRAS (G12D) is induced in mice. G12D) followed by adenomatous tumor nodules. RAS is a family of GTPase proto-oncogenes, comprising three closely related RAS isoforms: HRAS, KRAS and NRAS. From all of the RAS isoforms, KRAS is most frequently mutated, followed by NRAS and then HRAS. KRAS mutations are particularly frequent in the pancreatic, lung and colorectal cancers. In cancer, the most frequently mutated residues are G12, G13, and Q61. KRAS protein exists as two splice variants, KRAS4A and KRAS4B, in which KRAS4B is the dominant form in human cells. In the formulation of KRAS integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides KRAS-targeted drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services. https://www.medicilon.com/platform/kras/

The activation of KRAS signaling is a multi-step process that requires proper KRAS post-translation, plasma membrane-localization and interaction with effector proteins. In response to extracellular stimuli, the conversion from inactive RAS-GDP to active RAS-GTP further promotes the activation of various signaling pathways, which includes MAPK pathway, PI3K pathway and the Ral-GEFs pathway, among them the MAPK pathway is the best characterized. RAS-GTP directly binds to RAF protein, recruiting RAF kinase family from cytoplasm to membranes, where they dimerize and become active. The activated RAF subsequently carries out a chain of phosphorylation reactions to its downstream substrates, MEK and ERK, and propagates the growth signal. In the formulation of KRAS integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides KRAS-targeted drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services. Click for more: https://www.medicilon.com/platform/kras/

Topic: Unleashing the Potential of 3D Cultured Spheroids in Preclinical Research Outline: 1. Major steps and the business scope of Medicilon Inc. 2. Comparison between conventional tools and 3D in vitro approaches 3. Introduction to 3D culture techniques 4. Application of 3D spheroids in drug discovery 5. Case studies highlighting successful implementation

KRAS protein contains four domains. KRAS protein is made up of six beta-strands (forming the protein core) and five alpha-helices, which form two major domains: G-domain and C-terminal. The G domain of KRAS, comprised of residues 1-166, includes the GTP-binding pocket, a region within which is essential for the interactions between the putative downstream effectors and GTPase-activating proteins. https://www.medicilon.com/platform/kras/

RAS is a family of GTPase proto-oncogenes, comprising three closely related RAS isoforms: HRAS, KRAS and NRAS. From all of the RAS isoforms, KRAS is most frequently mutated. KRAS mutations are particularly frequent in the pancreatic, lung and colorectal cancers.

Based on their ability to activate GLP-1 receptor, GLP-1R agonists can be classified as short-acting and long-acting GLP-1R agonists. Short-acting GLP-1R agonists are require to give either a once-daily (QD) or twice-daily (BID) dosing (e.g., Exenatide and Lixisenatide). Long-acting GLP-1R agonists have undergone some structural modifications to enhance their duration of action, while retaining their ability to act on the GLP-1 receptors (e.g., Albiglutide, Dulaglutide, once weekly). https://www.medicilon.com/videos/glp-1r-agonists/

GLP-1 shows numerous actions in different tissues and a broad therapeutic potential. The main actions of GLP-1 are to stimulate insulin secretion and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. GLP-1 also causes weight loss by increasing satiety. In addition, GLP-1 also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. https://www.medicilon.com/videos/glp-1s-physiological-actions/

GLP-1 receptor agonists are now used for the treatment of type 2 diabetes and obesity. Looking back, GLP-1 was found to be a cleavage product of proglucagon processing.A key breakthrough came from the discovery of exendin-4.Exendin-4 is a peptide with agonistic properties at the GLP-1 receptor but resistance to degradation by DPP-4.Semaglutide, the first oral GLP-1 receptor agonist, marked the next milestone. https://www.medicilon.com/videos/glp-1-receptor-agonists-evolution/

After activation by full agonists such as GLP-1,GLP-1R(1)couples with Gas activates adenolate cyclase(AC),and causes the accumulation of cAMP.With increasing cAMP levels, protein kinase A（PKA） and the exchange protein directly activated by cAMP-2(Epac-2) are also activated. PKA and Epac-2 trigger the closure of KATP and KV channels,which depolarizes the cell membrane opens voltage-dependent Calcium channels(VDCC) and causes Calcium influx and the promotion of insulin secretion by the islet beta cells. https://www.medicilon.com/videos/mechanisms-of-glp-1/

GLP-1 New Drug R&D Service: Introduction of GLP-1s Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone. GLP-1 exists in two equally bioactive forms, GLP-1 (7-37) amide and GLP-1 (7-36) amide. GLP-1 is a biological product derived from the post-translational processing of proglucagon. GLP-1 is secreted by the enteroendocrine L cells, but also by some neuronal populations in the hindbrain. GLP-1 potentiates insulin release and reduces glucagon’s concentration in physiological conditions. https://www.medicilon.com/videos/glp-1s/

Medicilon's Pharmacology & Toxicology Study We boast professional teams and practical experience in drug safety evaluation and can promise high-quality data and fast turnaround time to support various drug safety evaluation. Our toxicology research can be carried out according to non-GLP or GLP standards. Our research platform has been rated as Shanghai R&D Public Service Platform. https://www.medicilon.com/videos/auc-repeated-adminitration-pktk/

For the low-dose tests， we are looking for a dose point that does not prove any adverse reactions in reproductive toxicity tests NOAEL. In doing so, we need to consider the exposure dose, pharmacology features, and toxicity and establish the proper dose-reaction relationship. In most cases, we set three doses for small molecule drugs and biotechnology therapies and two doses for vaccines to observe their reproductive toxicity. We'd suggest setting the low dose at 1-5 times the MRHD exposure dose. We also need to prove the rationality of our dose design if we decide to set the low dose at the level of the sub-therapeutic amounts. https://www.medicilon.com/videos/low-dose-in-reproductive-toxicity/

Medicilon's drug discovery module involves two research departments: Chemistry and Biology. https://www.medicilon.com/videos/Drug-Discovery/

Medicilon pre-clinical research services provide clients with the solutions to transform candidate compounds for clinical trial approval. Our integrated pre-clinical research services include PRE-CLINICAL SAFETY ASSESSMENT GLP & NON-GLP、 pharmacokinetic studies 、 Small Molecule Bioanalysis, and Large Molecule Bioanalysis, etc. https://www.medicilon.com/videos/Preclinical-Researche/

Medicilon's pharmaceutical research links clinical candidate compounds with commercialized medicine. By developing and improving APIs (Active Pharmaceutical Ingredients) and formulations, we provide our clients with a comprehensive process and quality control system that is both innovative and GMP-compliant. https://www.medicilon.com/videos/Pharmaceutical-Research/

In 2021, Medicilon established the International Discovery Service Unit (IDSU) to provide global pharmaceutical companies with high quality, high efficient and cost-effective chemistry synthesis design and production, medicinal chemistry, and the discovery and project delivery of clinical candidate compounds, which empowering global drug research and development. https://www.medicilon.com/videos/idsu/