98088-84-7Relevant academic research and scientific papers
Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
Du, Daohai,Xu, Dandan,Zhu, Licheng,Stazi, Giulia,Zwergel, Clemens,Liu, Yanli,Luo, Zhongyuan,Li, Yuanqing,Zhang, Yuanyuan,Zhu, Kongkai,Ding, Yiluan,Liu, Jingqiu,Fan, Shijie,Zhao, Kaiyan,Zhang, Naixia,Kong, Xiangqian,Jiang, Hualiang,Chen, Kaixian,Zhao, Kehao,Valente, Sergio,Min, Jinrong,Duan, Wenhu,Luo, Cheng
, p. 8194 - 8207 (2021/06/28)
Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 ?. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinityKdof 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action
Kumar, Malkeet,Okombo, John,Mambwe, Dickson,Taylor, Dale,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Fontinha, Diana,Sanches-Vaz, Margarida,Bezuidenhout, Belinda C.,Lauterbach, Sonja B.,Liebenberg, Dale,Birkholtz, Lyn-Marie,Coetzer, Theresa L.,Prudêncio, Miguel,Egan, Timothy J.,Wittlin, Sergio,Chibale, Kelly
, p. 303 - 315 (2019/01/15)
A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of 50 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.
Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds
Tian, Junjun,Vandermosten, Leen,Peigneur, Steve,Moreels, Lien,Rozenski, Jef,Tytgat, Jan,Herdewijn, Piet,Van den Steen, Philippe E.,De Jonghe, Steven
, p. 6332 - 6344 (2017/10/23)
Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
Discovery of the first nonpeptidic, Small-molecule, highly selective somatostatin receptor subtype 5 antagonists: A chemogenomics approach
Martin, Rainer E.,Green, Luke G.,Guba, Wolfgang,Kratochwil, Nicole,Christ, Andreas
, p. 6291 - 6294 (2008/03/30)
We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on the analysis of the homology of amino acids defining the putative consensus drug binding site of SST5R. With this strategy, opioid, histamine, dopamine, and serotonine receptors were identified as the closest neighbors of SST5R. The H1 antagonist astemizole was chosen as a seed structure and subsequently transformed into a SST5 receptor antagonist with nanomolar binding affinity devoid of the original target activity.
New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines
Janssens,Torremans,Janssen,Stokbroekx,Luyckx
, p. 1925 - 1933 (2007/10/02)
The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl) thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperideine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.
New Antihistaminic N-Heterocyclic 4-Piperidinamines. 2. Synthesis and Antihistaminic Activity of 1--N-(4-piperidinyl)-1H-benzimidazol-2-amines
Janssens, Frans,Torremans, Joseph,Janssen, Marcel,Stokbroekx, Raymond A.,Luyckx, Marcel,Janssen, Paul A. J.
, p. 1934 - 1943 (2007/10/02)
The synthesis of a series of 1--N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vivo antihistamine activity are described.The title compounds were obtained starting from either 1, 4, 10, or 55 by different synthetic methods.Substitution on the phenyl nucleus of the benzimidazole ring (84-87) was achieved by two different approaches.The in vivo antihistamine activity was evaluated by the compound 48/80 induced lethality test in rats and the antihistamine-induced lethality test in guinea pigs after oral and/o r subcutaneous administration.The duration of action was studied in the guinea pig for three compounds (4, 51, and 55).Compound 51, "astemizole", was also studied in histamine- and serotonin-induced cutaneous reaction and for mydriatic activity in the rat and tested for peripheral and central effects not related to histamine antagonism in a variety of systems.Astemizole has been selected for clinical investigation.
