56956-66-2Relevant academic research and scientific papers
Modulators of hERAP2 discovered by high-throughput screening
Laura, Medve,Ronan, Gealageas,Vy, Lam Bao,Valentin, Guillaume,Omar, Castillo-Aguilera,Virgyl, Camberlein,Piveteau, Catherine,Melissa, Rosell,Charlotte, Fleau,Sandrine, Warenghem,Julie, Charton,Julie, Dumont-Ryckembusch,Damien, Bosc,Florence, Leroux,Peter, van Endert,Benoit, Deprez,Rebecca, Deprez-Poulain
, (2020/12/29)
Endoplasmic reticulum aminopeptidase 2, ERAP2, is an emerging pharmacological target in cancer immunotherapy and control of autoinflammatory diseases, as it is involved in antigen processing. It has been linked to the risk of development of spondyloarthritis, and it associates with the immune infiltration of tumours and strongly predicts the overall survival for patients receiving check-point inhibitor therapy. While some selective inhibitors of its homolog ERAP1 are available, no selective modulator of ERAP2 has been disclosed so far. In order to identify such compounds, we screened an in-house focused library of 1920 compounds designed to target metalloenzymes. Structure-Activity Relationships and docking around two hits led to the discovery of selective inhibitors of ERAP2. Amid those, some bind to yet untapped amino-acids in the S1 pocket. Importantly, we disclose also the first activator of small substrates hydrolysis by ERAP2. Inhibitors and activators identified in this study could serve as useful starting points for optimization.
Structure-activity relationships of imidazole-derived 2-[ N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
Charton, Julie,Gauriot, Marion,Totobenazara, Jane,Hennuyer, Nathalie,Dumont, Julie,Bosc, Damien,Marechal, Xavier,Elbakali, Jamal,Herledan, Adrien,Wen, Xiaoan,Ronco, Cyril,Gras-Masse, Helene,Heninot, Antoine,Pottiez, Virginie,Landry, Valerie,Staels, Bart,Liang, Wenguang G.,Leroux, Florence,Tang, Wei-Jen,Deprez, Benoit,Deprez-Poulain, Rebecca
, p. 547 - 567 (2015/03/18)
Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.
Design, synthesis and structure-activity relationship studies of morpholino-1H-phenalene derivatives that antagonize Mcl-1/Bcl-2
Li, Xiangqian,Liang, Xiaomeng,Song, Ting,Su, Pengchen,Zhang, Zhichao
, p. 5738 - 5746 (2015/02/02)
We report herein characteristic studies of Mcl-1 and Bcl-2 dual inhibitors. It was found that a protruding carbonyl group forming hydrogen bond with R263 plays a predominant role compared with the hydrophobic group that occupies the p2 pocket. A series of dual inhibitors representing different parts of the morpholino-1H-phenalene were designed, synthesized and evaluated.
SYNTHESIS OF BAPTA-AM ANALOGUES CAPABLE OF ENHANCING THE VASCULAR PRODUCTION OF PROSTACYCLIN
Heilporn, S.,Broeders, F.,Daloze, D.,Braekman, J. C.,Boeynaems, J. M.
, p. 309 - 320 (2007/10/02)
About 30 analogues of BAPTA-AM, a potential antithrombotic agent, have been synthesized and tested for their effect on the production of prostacyclin.None of them was found to be a better enhancher of the production of prostacyclin by aortic endothelial cells than BAPTA-AM itself.The enhancing effect can be produced by compounds unable to chelate Ca2+, thus confirming that it is not related to their buffering capacity for free Ca2+.
