Pathway Inhibitors

The PI3K/Akt/mTOR pathway controls many cellular processes that are important for the formation and progression of cancer, including apoptosis, transcription, translation, metabolism, angiogenesis, and cell cycle progression. Every major node of this signaling network is activated in a wide range of human tumors. Mechanisms for the pathway activation include activation of receptor tyrosine kinases (RTKs) upstream of PI3K, mutation or amplification of PIK3CA encoding p110α catalytic subunit of PI3K, mutation or loss of PTEN tumor suppressor gene, and mutation or amplification of Akt1. Once the pathway is activated, signaling through Akt can stimulate a series of substrates including mTOR which is involved in protein synthesis. Thus, inhibition of this pathway is an attractive concept for cancer prevention and/or therapy. Currently some mTOR inhibitors are approved for several indications, and there are several novel PI3K/Akt/mTOR inhibitors in clinical trials.

MCE owns a unique collection of 568 compounds that can be used for PI3K/Akt/mTOR pathway research. PI3K/Akt/mTOR Compound Library also acts as a useful tool for anti-cancer drug discovery.

Mutations in oncogenes and tumor suppressor genes can modify multiple signaling pathways and in turn cell metabolism, which facilitates tumorigenesis. The paramount hallmark of tumor metabolism is “aerobic glycolysis” or the Warburg effect, coined by Otto Warburg in 1926, in which cancer cells produce most of energy from glycolysis pathway regardless of whether in aerobic or anaerobic condition. Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside. The increased uptake of glucose is facilitated by the overexpression of several isoforms of membrane glucose transporters (GLUTs). Likewise, the metabolic pathways of glutamine, amino acid and fat metabolism are also altered. Recent trends in anti-cancer drug discovery suggests that targeting the altered metabolic pathways of cancer cells result in energy crisis inside the cancer cells and can selectively inhibit cancer cell proliferation by delaying or suppressing tumor growth.

MCE provides a unique collection of 2043 compounds which cover various tumor metabolism-related signaling pathways. These compounds can be used for anti-cancer metabolism targets identification, validation as well anti-cancer drug discovery.

Stem cells, which are found in all multi-cellular organisms, can divide and differentiate into diverse special cell types and can self-renew to produce more stem cells. To be useful in therapy, stem cells must be converted into desired cell types as necessary which is called induced differentiation or directed differentiation. Understanding and using signaling pathways for differentiation is an important method in successful regenerative medicine. Small molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal molecules and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs); the wnt family or superfamily of transforming growth factors β (TGFβ) and bone morphogenetic proteins (BMP). Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These small molecules can be used for either activating or deactivating specific signaling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

MCE Differentiation Inducing Compound Library contains a unique collection of 1436 compounds that act on signaling pathways for differentiation. These compounds are potential stimulators for induced differentiation. This library is a useful tool for researching directed differentiation and regenerative medicine.

The developmental proteins Hedgehog, Notch and Wnt are key regulators of cell fate, proliferation, migration and differentiation in several tissues. Their related signaling pathways are frequently activated in tumors, and particularly in the rare subpopulation of cancer stem cells. The Wnt signaling pathway is a conserved pathway in animals. Deregulated Wnt signaling has catastrophic consequences for the developing embryo and it is now well appreciated that defective Wnt signaling is a causative factor for a number of pleiotropic human pathologies, including cancer. Hedgehog signaling pathway is linked to tumorigenesis and is aberrantly activated in a variety of cancers. The Notch signaling pathway is a highly conserved cell signaling system present in most animals. It plays an important role in cell-cell communication, and further regulates embryonic development.

MCE designs a unique collection of 352 Wnt/Hedgehog/Notch signaling pathway-related small molecules. Wnt/Hedgehog/Notch Compound Library serves as a useful tool for stem cell research and anti-cancer drug screening.

MAPK families play an important role in complex cellular programs like proliferation, differentiation, development, transformation, and apoptosis. In mammalian cells, four MAPK families have been clearly characterized: ERK1/2, C-Jun N-terminal kinse/stress-activated protein kinase (JNK/SAPK) , p38 kinase and ERK5. They respond to different signals. Each MAPK-related cascade consists of three enzymes that are activated in series: a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK) and a MAP kinase (MAPK). MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers.

MCE designs a unique collection of 510 MAPK signaling pathway inhibitors that act as a useful tool for MAPK-related drug screening and disease research.

Adult stem cells are important for tissue homeostasis and regeneration due to their ability to self-renew and generate multiple types of differentiated daughters. Self-renewal is reflected by their capacity to undergo multiple/limitless divisions. Several signaling pathways are involved in self-renewal of stem cells, that is, Notch, Wnt, and Hedgehog pathways or Polycomb family proteins. Recent studies mainly focus on cancer stem cell (CSCs), induced pluripotent stem cell (iPSCs), neural stem cell and maintenance of embryonic stem cell pluripotency. Among them, CSCs have been believed to be responsible for tumor initiation, growth, and recurrence that have implications for cancer therapy.

MCE owns a unique collection of 1740 compounds that can be used for stem cell regulatory and signaling pathway research.

Coagulation, also known as clotting, is the process in which blood changes from a liquid to a solid gel to form a blood clot. Thrombin, which is accurately and evenly generated in the injured part of blood vessels, is a key effector enzyme of the blood coagulation system and participates in many important biological processes, such as platelet activation, fibrinogen conversion to fibrin network, coagulation feedback amplification, etc. At the same time, to avoid the accidental formation of thrombus in the body, there is also an anticoagulant mechanism that inhibits blood coagulation.

Normal coagulation mechanism represents a balance between the pro-coagulant pathway in the injured site and anti-coagulant pathway beyond it. The blood coagulation system may be out of balance during the perioperative period or critical illness, which may lead to thrombosis or excessive bleeding. Therefore, the physiological study of coagulation balance is an important basis for clinical diagnosis and treatment of the abnormal coagulation process.

MCE supplies a unique collection of 965 compounds targeting key proteins in coagulation and anti-coagulation system. MCE Coagulation and Anti-coagulation Compound Library is a useful tool for study the mechanism of coagulation and anticoagulation.

Nuclear factor-κB (NF-κB)/Rel proteins include NF-κB2 p52/p100, NF-κB1 p50/p105, c-Rel, RelA/p65, and RelB. These proteins function as dimeric transcription factors that regulate the expression of genes and influence a broad range of biological processes including innate and adaptive immunity, inflammation, stress responses, B-cell development, and lymphoid organogenesis. NF-κB plays a key role in regulating the immune response to infection. In addition, activation of the NF-κB pathway is involved in the pathogenesis of chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.

MCE owns a unique collection of 805 small molecule compounds that can be used in the research of NF-κB signaling pathway or high throughput screening (HTS) related drug discovery.

The majority of hypertensive patients have primary (or essential) hypertension, that is, hypertension in which secondary causes are not present. Management aims to control arterial pressure, prevent end-organ damage (cerebrovascular, cardiovascular, and renal), and reduce the risk of premature death.

Antihypertensive drugs may be divided into two broad groups, the first group being those which directly or indirectly block the renin–angiotensin system (RAS), for example, ACEIs, angiotensin receptor antagonists (ARAs), direct renin inhibitors (DRIs), and to a lesser extent β-blockers. The second group of drugs works by increasing water and sodium excretion, thereby reducing intravascular volume, or by causing vasodilatation through non-RAS pathways, for example, diuretics and calcium channel blockers (CCBs).

MCE offers a unique collection of 481 compounds with identified and potential antihypertensive activity. MCE Antihypertensive Compound Library is critical for antihypertensive drug discovery and development.

The TCA cycle (tricarboxylic acid cycle)—is also known as the Krebs cycle or the citric acid cycle (CAC). The TCA cycle is a series of chemical reactions that release stored energy through the oxidation of acetyl-CoA in carbohydrates, fats, and proteins.

For decades, the TCA cycle has been considered as the central pathway for cell oxidative phosphorylation to produce energy and biosynthesis. Research shows that TCA cycle is associated with many diseases, especially cancer. In colon carcinoma, liver cancer and other cancers, there are mutations that lead to the imbalance of TCA cycle metabolites, indicating that TCA cycle may be related to the occurrence of cancer. Understanding the role and molecular mechanism of TCA cycle in inhibiting or promoting cancer progression will promote the development of new metabolite-based cancer treatment methods in the future.

MCE supplies a unique collection of 65 compounds related to the TCA cycle. MCE TCA Cycle Compound Library is a useful tool for the TCA cycle related research and anti-cancer drug development.

Glycolysis is a series of metabolic processes by which one molecule of glucose is catabolized to two molecules of pyruvate with a net gain of two ATP. Glycolysis takes place in 10 steps and catalyzed by a series of enzyme, such as hexokinase, Glucose-6-phosphate isomerase, Phosphofructokinase, etc. Glycolysis is used by all cells in the body for energy generation.

Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

MCE provides a unique collection of 689 glycolysis compounds that mainly target hexokinase, glucokinase, enolase, pyruvate kinase, PDHK, etc. MCE Glycolysis Compound Library is a useful tool for glucose metabolism research and anti-cancer drug discovery.

Copper is an important co-factor of all biological enzymes, but if the concentration exceeds the threshold of maintaining the homeostasis mechanism, copper will lead to cytotoxicity. This death mechanism has been named "Cuproptosis".

The mechanism of cuproptosis distinct from all other known mechanisms of regulated cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis.

Copper combine with the lipoylated components of the tricarboxylic acid cycle (TCA), leading to lipoylated protein aggregation and subsequent loss of iron-sulfur cluster proteins, ultimately resulting in protein toxicity stress and cell death. Studies have shown that the necessary factors for cuproptosis include the presence of glutathione, mitochondrial metabolism of galactose and pyruvate, and glutamine metabolism.

Targeted regulation of cuproptosis is a potential choice to treat cancer, rheumatoid arthritis, and other diseases. For example, up-regulation of LIPT1 may inhibit the occurrence and development of tumors by destroying TCA in mitochondria and then inducing cuproptosis.

MCE supplies a unique collection of 187 cuproptosis-related compounds, all of which act on the targets or signaling pathways related to cuproptosis and may have in inhibitory or activated effect on cuproptosis. MCE Cuproptosis Library is a useful tool for drug research related to cancer, rheumatoid arthritis, and other diseases.