The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

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Kynurenines in the mammalian brain: when physiology meets pathology

Antibody molecules that specifically bind to PD-1 are disclosed. The anti-PD-1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.

Antibody molecules to pd-1 and uses thereof

Purpose: The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. Experimental Design: Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments. Results: INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET–dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET–dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro . Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET–driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. Conclusions: Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment. Clin Cancer Res; 17(22); 7127–38. ©2011 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/17/22/7127.full.pdf

A Novel Kinase Inhibitor, INCB28060, Blocks c-MET–Dependent Signaling, Neoplastic Activities, and Cross-Talk with EGFR and HER-3

Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered clinical trials. However, a significant number of the reported compounds contain problematic functional groups, suggesting that enzyme inhibition could be the result of undesirable side reactions instead of selective binding to IDO1. Here, we describe issues in the employed experimental protocols, review and classify reported IDO1 inhibitors, and suggest different approaches for confirming viable inhibitor scaffolds.

https://pubsdc3.acs.org/doi/pdfplus/10.1021/acs.jmedchem.5b00326

Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2', 5', 2', 5' and 2', 5 ',3 ',5' CDNs, and prefereably Rp,Rp stereosiomers thereof.

Compositions and methods for activating "stimulator of interferon gene"-dependent signalling

The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

1,2,5-Oxadiazoles As Inhibitors Of Indoleamine 2,3-Dioxygenase

The present invention is directed to dihydrochloric acid and dibenzenesulfonic acid salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and pharmaceutical compositions thereof, useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. The present invention further relates to processes and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and salts thereof.

SALTS OF 2-FLUORO-N-METHYL-4-[7-(QUINOLIN-6-YL-METHYL)-IMIDAZO[1,2-b][1,2,4]TRIAZIN-2-YL]BENZAMIDE AND PROCESSES RELATED TO PREPARING THE SAME

The present application is directed to processes and intermediates for making (S)-7-(1-((9H-purin-6-yl)amino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, which is an inhibitor of phosphoinositide 3-kinases (PI3Ks), useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

Process for the synthesis of a phosphoinositide 3-kinase inhibitor

La presente invention concerne des procedes et des intermediaires de fabrication de 4-({2- [(aminosulfonyl) amino]ethyl}amino)- N -(3-bromo-4-fluorophenyl)- N' -hydroxy-1,2,5-oxadiazole-3-carboximidamide, qui est un inhibiteur de l'indoleamine 2,3-dioxygenase, utiles dans le traitement du cancer et d'autres troubles.

Procédé pour la synthèse d'un inhibiteur de l'indoleamine 2,3-dioxygénase

La presente invention concerne des sels d’acide dichlorhydrique et d’acide dibenzenesulfonique de l’inhibiteur de c-Met kinase, le 2-fluoro-N-methyl-4-[7-(quinolein-6-ylmethyl)-imidazo[1,2-b][1,2,4]- triazin-2-yl]benzamide, et leurs compositions pharmaceutiques, utiles dans le traitement du cancer et d’autres maladies associees au dereglement des voies des kinases. La presente invention concerne en outre des procedes et des intermediaires de preparation du 2-fluoro-N-methyl-4-[7-(quinolein-6-ylmethyl)imidazo[1,2-b][1,2,4]- triazin-2-yl]benzamide et de ses sels.

Lingkai Weng

Papers

1,2,5-Oxadiazoles As Inhibitors Of Indoleamine 2,3-Dioxygenase

SALTS OF 2-FLUORO-N-METHYL-4-[7-(QUINOLIN-6-YL-METHYL)-IMIDAZO[1,2-b][1,2,4]TRIAZIN-2-YL]BENZAMIDE AND PROCESSES RELATED TO PREPARING THE SAME

Process for the synthesis of a phosphoinositide 3-kinase inhibitor

Procédé pour la synthèse d'un inhibiteur de l'indoleamine 2,3-dioxygénase

Sels de 2-fluoro-n-méthyl-4-[7-(quinoléin-6-yl-méthyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide et procédés associés à leur préparation