1429129-61-2Relevant academic research and scientific papers
BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability
Jennings, Laura E.,Schiedel, Matthias,Hewings, David S.,Picaud, Sarah,Laurin, Corentine M.C.,Bruno, Paul A.,Bluck, Joseph P.,Scorah, Amy R.,See, Larissa,Reynolds, Jessica K.,Moroglu, Mustafa,Mistry, Ishna N.,Hicks, Amy,Guzanov, Pavel,Clayton, James,Evans, Charles N.G.,Stazi, Giulia,Biggin, Philip C.,Mapp, Anna K.,Hammond, Ester M.,Humphreys, Philip G.,Filippakopoulos, Panagis,Conway, Stuart J.
, p. 2937 - 2957 (2018)
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t? = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t? = 388 min).
COMPOUND WITH ANTICANCER ACTIVITY
-
Paragraph 1361, (2021/01/29)
A compound having anticancer activity, or a pharmaceutically acceptable salt thereof is provided. Used is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: (wherein, L1 and L2 are the same or different and each represents a group represented by one formula selected from the group consisting of formulas (A) to (F), and S represents a group represented by one formula selected from the group consisting of formulas (S1) to (S18)).
Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3,5-dimethylisoxazole
Yang, Lingyun,Zhang, Jian,Si, Lianghui,Han, Li,Zhang, Bo,Ma, Hui,Xing, Junhao,Zhao, Leilei,Zhou, Jinpei,Zhang, Huibin
, p. 46 - 58 (2016/04/19)
GPR40 is an attractive target due to its glucose-stimulated insulin secretion effect with low risk of causing hypoglycemia, which also can be seen from the clinical studies using TAK-875 (fasiglifam). In the present studies, we discovered a series of anal
Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands
Hewings, David S.,Fedorov, Oleg,Filippakopoulos, Panagis,Martin, Sarah,Picaud, Sarah,Tumber, Anthony,Wells, Christopher,Olcina, Monica M.,Freeman, Katherine,Gill, Andrew,Ritchie, Alison J.,Sheppard, David W.,Russell, Angela J.,Hammond, Ester M.,Knapp, Stefan,Brennan, Paul E.,Conway, Stuart J.
, p. 3217 - 3227 (2013/06/04)
The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodom
