63555-50-0Relevant articles and documents
Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1
Maben, Zachary,Arya, Richa,Rane, Digamber,An, W. Frank,Metkar, Shailesh,Hickey, Marc,Bender, Samantha,Ali, Akbar,Nguyen, Tina T.,Evnouchidou, Irini,Schilling, Roger,Stratikos, Efstratios,Golden, Jennifer,Stern, Lawrence J.
, p. 103 - 121 (2020/02/20)
ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1's hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively inhibits its activity toward a nonamer peptide representative of physiological substrates. Compounds 2 and 3 inhibit antigen presentation in a cellular assay. Compound 3 displays higher potency for an ERAP1 variant associated with increased risk of autoimmune disease. These inhibitors provide mechanistic insights into the determinants of specificity for ERAP1, ERAP2, and IRAP and offer a new therapeutic approach of specifically inhibiting ERAP1 activity in vivo.
Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer
Zhang, Kuojun,Ni, Yong,Chen, Jiaxuan,Tu, Zhengchao,Wu, Xiaoxing,Chen, Dong,Yao, Hequan,Jiang, Sheng
, p. 1502 - 1506 (2019/04/17)
Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC50 = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC50 values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC50 values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors
Zhao, Chunlong,Zang, Jie,Ding, Qin'ge,Inks, Elizabeth S.,Xu, Wenfang,Chou, C. James,Zhang, Yingjie
, p. 282 - 291 (2018/03/21)
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (～30-fold) which was confirmed by western blot analysis. It is worth noting that 12a, 12b and 12c displayed highly selective anti-proliferative activity to T-cell leukemia cell lines Jurkat, Molt-4 and neuroblastoma cell line SK-N-BE-(2). Such selective cytotoxicity was also observed in the well-known HDAC8 selective inhibitor PCI-34051 but not in the pan-HDAC inhibitors SAHA and PXD101, indicating that HDAC8 selective inhibitor should have preferable benefit-risk profile in comparison with pan-HDAC inhibitor. Finally, the HDAC8 selectivity of 12a, 12b and 12c was rationalized by molecular docking study.
