suppressors

Nucleotide metabolism is central to cancer aggressiveness, underpinning uncontrolled proliferation, chemotherapy resistance, immune evasion, and metastasis. It is transcriptionally regulated by oncogenes (e.g., MYC) and tumor suppressors (e.g., pRb). Nucleotide imbalance and nucleoside degradation further regulate cell state transitions, especially following replication stress. Additionally, secretion of nucleotides/nucleosides into the tumor microenvironment modulates immune responses and influences treatment efficacy. Therefore, nucleotide metabolites have roles in disease response and indication in cancer research, and can be utilized to develop cancer-related mechanisms and drugs.

MCE can provide 82 metabolites produced by nucleotide metabolic pathways, which can be used for disease mechanism research and drug research.

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. PROTACs consist of a ligand for E3 ligase (E3 ligase binder), a linker and a ligand (mostly small-molecule inhibitor) for protein of interest（target binder）. Upon binding to the target protein, the PROTACs can recruit E3 for target protein ubiquitination, which is subjected to proteasome-mediated degradation.

Although there are more than 600 E3 ubiquitin ligases, only several with small molecule ligands have been used for designing PROTACs, including Skp1-Cullin-F box complex containing Hrt1 (SCF), Von Hippel-Lindau tumor suppressor (VHL), Cereblon (CRBN), inhibitor of apoptosis proteins (IAPs), and mouse double minute 2 homolog (MDM2).

MCE carefully prepared a unique collection of 174 ligands for E3 ligase, which have been reported to be used in PROTAC design. MCE E3 ligase ligand library is a useful tool for PROTAC development.

Liver cancer is one of the leading malignancies which occupies the second position in cancer deaths worldwide, becoming serious threat to human health. Hepatocellular carcinoma (HCC), also known as hepatoma is the most common type accounting for approximately 90% of all liver cancers.

Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These include the RAF/MEK/ERK pathway, PI3K/AKT/mTOR pathway, WNT/b-catenin pathway, insulin-like growth factor pathway, c-MET/HGFR pathway , etc.

MCE offers a unique collection of 2,838 compounds with identified and potential anti-liver cancer activity. MCE anti-liver cancer compound library is a useful tool for anti-liver cancer drugs screening and other related research.

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 3,552 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.

Glutamine is an important metabolic fuel that helps rapidly proliferating cells meet the increased demand for ATP, biosynthetic precursors, and reducing agents. Glutamine Metabolism pathway involves the initial deamination of glutamine by glutaminase(GLS), yielding glutamate and ammonia. Glutamate is converted to the TCA cycle intermediate α-ketoglutarate (α-KG) by either glutamate dehydrogenase (GDH) or by the alanine or aspartate transaminases (TAs), to produce both ATP and anabolic carbons for the synthesis of amino acids, nucleotides and lipids. During periods of hypoxia or mitochondrial dysfunction, α-KG can be converted to citrate in a reductive carboxylation reaction catalyzed by IDH2. The newly formed citrate exits the mitochondria where it is used to synthesize fatty acids and amino acids and produce the reducing agent, NADPH.

Cancer cells display an altered metabolic circuitry that is directly regulated by oncogenic mutations and loss of tumor suppressors. Mounting evidence indicates that altered glutamine metabolism in cancer cells has critical roles in supporting macromolecule biosynthesis, regulating signaling pathways, and maintaining redox homeostasis, all of which contribute to cancer cell proliferation and survival. Thus, intervention in glutamine metabolic processes could provide novel approaches to improve cancer treatment.

MCE owns a unique collection of 1,690 compounds targeting the mainly proteins and enzymes involved in glutamine metabolism pathway. Glutamine Metabolism compound library is a useful tool for intervention in glutamine metabolic processes.

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 1,049 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.

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. A variety of HF-1 target genes have been identified thus far which encode proteins that play key roles in critical developmental and physiological processes including angiogenesis/vascular remodeling, erythropoiesis, glucose transport, glycolysis, iron transport, and cell proliferation/survival.

HIF-1 is a heterodimeric transcription factor consisting of a constitutively expressed β-subunit and an oxygen-regulated α-subunit. The unique feature of HIF-1 is the regulation of HIF-1α expression and activity based upon the cellular O₂ concentration. Under normoxic conditions, hydroxylation of HIF-1α on these different proline residues is essential for HIF proteolytic degradation by promoting interaction with the von Hippel-Lindau tumor-suppressor protein (pVHL) through hydrogen bonding to the hydroxyproline-binding pocket in the pVHL β-domain. As oxygen levels decrease, hydroxylation of HIF decreases; HIF-1α then no longer binds pVHL, and becomes stabilized, allowing more of the protein to translocate to the cell’s nucleus, where it acts as a transcription factor, upregulating (often within minutes) the production of proteins that stimulate blood perfusion in tissues and thus tissue oxygenation.

MCE offers a unique collection of 4,029 oxygen sensing related compounds targeting HIF/HIF Prolyl-Hydroxylase, MAPK/ERK, PI3K/AKT signaling pathways, etc. MCE Oxygen Sensing Compound Library is a useful tool to study hypoxia, oxidative stress and discover new anti-cancer drugs.