6188-23-4Relevant articles and documents
From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
, p. 1197 - 1219 (2021/02/05)
Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
Design, synthesis and biological evaluation of imidazopyridazine derivatives containing isoquinoline group as potent MNK1/2 inhibitors
Bu, Hong,Yuan, Xinrui,Wu, Hanshu,Zhou, Jinpei,Zhang, Huibin
, (2021/05/13)
Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively. MNKs modulate the translation of mRNA involved in tumor-associated signaling pathways. Consequently, selective inhibitors of MNK1/2 could reduce the level of phosphorylated eIF4E. Series of imidazopyrazines, imidazopyridazines and imidazopyridines derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against diffuse large B-cell lymphoma (DLBCL) cell lines. In particular, compound II-5 (MNK1 IC50 = 2.3 nM; MNK2 IC50 = 3.4 nM) exhibited excellent enzymatic inhibitory potency and proved to be the most potent compound against TMD-8 and DOHH-2 cell lines with IC50 value of 0.3896 μM and 0.4092 μM respectively. These results demonstrated that compound II-5 could be considered as a potential MNK1/2 inhibitor for further investigation.
Design, Synthesis, and Biological Evaluation of Imidazo[1,2- a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors
Yu, Ya'Nan,Han, Yuqiao,Zhang, Fupo,Gao, Zhenmei,Zhu, Tong,Dong, Suzhen,Ma, Mingliang
, p. 3028 - 3046 (2020/04/09)
PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.