19492-95-6Relevant articles and documents
Ring closure strategy leads to potent RIPK3 inhibitors
Wu, Shuwei,Xu, Chen,Xia, Kaijiang,Lin, Yu,Tian, Sheng,Ma, Haikuo,Ji, Yuting,Zhu, Fang,He, Sudan,Zhang, Xiaohu
, (2021/03/16)
Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound 38 exhibited potent activity (EC50 = 0.42 μM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29 cells. Mechanistic studies showed that compound 38 bound to RIPK3 with high affinity (Kd = 7.1 nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound 38 displayed good selectivity over another necroptosis regulator RIPK1 (Kd = 6000 nM). Furthermore, compound 38 demonstrated excellent in vitro safety profiles with minimal inhibition of CYP isozymes and hERG potassium channel. Lastly, compound 38 efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.
Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach
Chen, Chao,Zhu, Hugh,Stauffer, Frédéric,Caravatti, Giorgio,Vollmer, Susanne,Machauer, Rainer,Holzer, Philipp,M?bitz, Henrik,Scheufler, Clemens,Klumpp, Martin,Tiedt, Ralph,Beyer, Kim S.,Calkins, Keith,Guthy, Daniel,Kiffe, Michael,Zhang, Jeff,Gaul, Christoph
, p. 735 - 740 (2016/08/24)
Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.
