​Prostanoids are established mediators of inflammation, and the therapeutic efficacy of drugs that block their global biosynthesis in conditions such as rheumatoid arthritis is well-known. AGN 225660 blocks pro-inflammatory prostanoid receptors (DP1, EP1, EP4, FP, TP). AGN 225660 represents a second-generation compound with an “druggable” core structure. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, lipopolysaccharide (LPS), and arachidonic acid induced uveitis. Ocular Pharmacokinetic studies were performed at Medicilon.

Colorectal cancer (CRC) is the leading cause of cancer death; however, targets with broad anti-CRC effects are limited. Sirtuin6 (SIRT6) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that is widely pathologically downregulated in CRC. MDL-811, an allosteric SIRT6 activator, enhances SIRT6 deacetylation. Pharmacokinetic studies were performed by Shanghai Medicilon Inc, China, following standard protocols.

Gastric cancer (GC) is one of the most common malignancies and is the leading global cause of death by cancer. Over recent decades, targeted therapies and immunotherapy have become significant new approaches for the treatment of GC. Ferroptosis is a newly verified form of modulated cell death that is characterized by lipid peroxidation. Further exploration of the function of ferroptosis in the progression of GC has provided novel opportunities for diagnosis and treatment. The overexpression of MGST1 induced the activation of the Akt/GSK-3β pathway. An Akt inhibitor antagonized the inhibitory effects of MGST1 on autophagy and ferroptosis. MGST1 and ATG16L1 overexpression, and MGST1 depletion assay were conducted by Medicilon.

Cell division cycle 7 (CDC7), a serine/threonine kinase, plays important roles in the initiation of DNA replication. TAK-931, a highly specific CDC7 inhibitor, acts as a next-generation of replication stress (RS) inducer. Combination treatment with TAK-931 and immune checkpoint inhibitors (ICIs) enhances antiproliferative activities in preclinical syngeneic mouse models. The flowcytometry (FCM)-based immune profiling panel studies in J558 allograft syngeneic mouse models were performed at Medicilon. In vivo efficacy studies in J558 allograft models in combination with anti-mPD-1, anti-mPD-L1, and anti-mCTLA-4 antibodies were performed at Medicilon. Therapeutic potential of TAK-931 in antitumor efficacy and immunity, which may improve clinical benefit of the currently-used immunotherapy by combination treatment.

Chrysin is a natural flavonoid that has been reported as a potential treatment for non-alcoholic fatty liver disease (NAFLD). Researchers synthesized a novel chrysin derivative prodrug (C-1) and further investigated its potential therapeutic mechanism against NAFLD in vitro and in vivo. C-1 had a low toxicity profile. Their data demonstrated that C-1 may be a promising agent for NAFLD therapy. Evaluation experiments of the acute toxicities of C-1 were conducted by Medicilon.

Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has attracted attention as a target. Researchers have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 demonstrated marked, dose-dependent antitumor activity, without severe body weight loss. Antitumor efficacy studies for TAK-931 were carried out in two pancreatic PDX models, PHTX-249Pa and PHTXM-97Pa, at Medicilon.

​Alzheimer's disease (AD) is the most universal age-related neurodegenerative disease. AP39 is a newly synthesized mitochondrially targeted H2S donor on mitochondrial function. AP39 increases intracellular H2S levels, mainly in mitochondrial regions. AP39 exerts dose-dependent effects on mitochondrial activity in APP/PS1 neurons. AP39, a novel mitochondria-targeted H2S donor, was designed and synthesized by Medicilon.

Alzheimer's disease (AD) is a progressive and devastating neurodegenerative disorder, characterized by the presence of β-amyloid (Aβ) peptide plaques, neurofibrillary tangles, and neuroinflammation. Receptor for advanced glycation end products (RAGE) belongs to the immunoglobulin superfamily, which functions as a cell surface acceptor for Aβ peptide. RAGE plays an important role in the Aβ-mediated neuronal damage that closely related to the pathogenesis of AD. In this study, Compound 12 showed good dual-target bioactivities against RAGE and SERT in vitro, good liver microsomal stability, and acceptable pharmacokinetic properties. Pharmacokinetic studies were commissioned by Medicilon.

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics “readers”and potential therapeutic targets for cancer and other diseases. Y08624 (Compound 20l) is a new TRIM24/BRPF1 dual inhibitor. Y08624 displays reasonable Caco-2 permeability. Caco-2 permeability assay was performed by Medicilon.

Apoptosis is a cellular process critical to the normal development and homeostasis of multicellular organisms. The inhibitor of apoptosis proteins (IAPs) are a class of key apoptosis regulators. IAP proteins are attractive cancer therapeutic targets. SM-406 (compound 2) is a potent and orally bioavailable antagonist of the IAPs. Pharmacokinetic (PK) studies of SM-406 (compound 2) in male Sprague Dawley rats, beagle dogs and cynomolgus monkeys (non-human primates) were performed by the Division of Pharmacokinetics and Metabolism, Medicilon. SM-406 (compound 2) has an excellent PK profile and good oral bioavailability in each of these four species.