27830-16-6Relevant articles and documents
Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents
Priebbenow, Daniel L.,Leaver, David J.,Nguyen, Nghi,Cleary, Benjamin,Lagiakos, H. Rachel,Sanchez, Julie,Xue, Lian,Huang, Fei,Sun, Yuxin,Mujumdar, Prashant,Mudududdla, Ramesh,Varghese, Swapna,Teguh, Silvia,Charman, Susan A.,White, Karen L.,Shackleford, David M.,Katneni, Kasiram,Cuellar, Matthew,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Street, Ian P.,Monahan, Brendon J.,Jarman, Kate E.,Jousset Sabroux, Helene,Falk, Hendrik,Chung, Matthew C.,Hermans, Stefan J.,Downer, Natalie L.,Parker, Michael W.,Voss, Anne K.,Thomas, Tim,Baell, Jonathan B.
, p. 4655 - 4684 (2020/06/08)
A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.
Structure activity relationship of brevenal hydrazide derivatives
Goodman, Allan,McCall, Jennifer R.,Jacocks, Henry M.,Thompson, Alysha,Baden, Daniel,Abraham, William M.,Bourdelais, Andrea
, p. 1839 - 1858 (2014/06/09)
Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.
