Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an ...active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure–activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure–activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His55 and Thr254 residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K i = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an ...active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.
The inhibition of indoleamine 2,3-dioxygenase (IDO) has emerged as a key area in cancer immunotherapy in the past decade. Despite the large variety of potential inhibitors screened so far, the number ...of active scaffolds remains limited.
All relevant patent literature published between 2008 and 2012 is reviewed. Representative examples are given for each patent and/or class of compounds along with data (if available) on their inhibitory activity. The presentation is deepened by additional data published in peer-reviewed literature.
Key events that stimulated the search of IDO inhibitors are presented. To date, however, the number of available scaffolds remains limited with only one confirmed inhibitor (from Incyte Corp.) in the clinic. Major challenges in the search for IDO inhibitors are discussed as well as the relevance of selectivity of IDO inhibition versus inhibition of tryptophan 2,3-dioxygenase.
Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood ...coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds.
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•3-carboxamide coumarins were previously described as selective FXIIa inhibitors.•New 3-carboxamide coumarins were synthesized and assessed.•An original FXIIa hybrid model was built to carry out a molecular modeling study.•This study helped to better understand the activity and selectivity on FXIIa.
The present study describes the optimization of a new method of synthesis of highly functionalized 5-bromo-2-amino-1,3-thiazoles by a rapid and efficient one-pot method, using simple starting ...materials and mild conditions. Interestingly some of the synthesized compounds demonstrate promising monoacylglycerol lipase inhibition properties.
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•Convenient one-pot synthesis of highly functionalized 5-bromo-2-amino-1,3-thiazoles.•Potential MAGL inhibitors.•Safe and efficient bromination reaction.
Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents could be easily prepared by a rapid and efficient one-pot method, using simple starting materials and mild conditions while avoiding the use of metal catalysts or inconvenient reagents such as elemental halogens. These useful products can serve as starting materials for other reactions or as pharmacologically interesting compounds. In our work we have shown that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL) inhibition in the μM range.
Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the ...discovery of the keto-indole derivative
1a endowed with an inhibitory potency in the micromolar range. Detailed kinetics were performed and revealed an uncompetitive inhibition profile. Preliminary SARs were drawn in this series and corroborated the putative binding orientation as suggested by docking.
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► Indoleamine 2,3-dioxygenase (IDO) involved in anticancer immunosuppression. ► Keto-indoles are novel IDO inhibitors. ► Substitution in the 5-position allows to enhance IDO inhibition. ► Keto-indoles act as uncompetitive inhibitors.
Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological ...properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity.
Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors.
Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure–activity ...relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC50 values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.
Here, we report on an ion-channel mimetic sensor using self-assembly monolayers deposited onto gold electrodes for electrochemical determination of dopamine. The different compositions of the ...modification solution consist of corrole-SH and other thiol derivatives used as the “background compounds” such as 1-dodecanethiol (DDT), 6-mercapto-1-hexanol (HS(CH2)6OH), or 11-mercapto-1-undecanol (HS(CH2)11OH) were explored to find the best self-assembled monolayer (SAM) suitable for dopamine determination. Among them, the mixed SAM consisting of corroles with the −SH group and 6-mercapto-1-hexanol (HS(CH2)6OH) in the molar ratio 1:10 was the most sensitive. The signals generated by the formation of a complex between the corrole host and the dopamine guest were measured by Osteryoung square-wave voltammetry (OSWV) and electrochemical impedance spectroscopy (EIS) with Ru(NH3)63+ as an electroactive marker. The developed sensor was free of interferences of components of human plasma such as ascorbic acid, creatinine, creatine, and uric acid. The detection limits observed by EIS in buffer solution and in the presence of centrifuged human plasma 80 times diluted with a 0.9% NaCl containing 0.01 M borate buffer solution of pH 7.0 were 3.3 × 10−12 and 5.3 × 10−12 M, respectively.
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