112887-25-9Relevant articles and documents
Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods
Sarkar, Dhruba,Olejniczak, Edward T.,Phan, Jason,Coker, Jesse A.,Sai, Jiqing,Arnold, Allison,Beesetty, Yugandhar,Waterson, Alex G.,Fesik, Stephen W.
, p. 8325 - 8337 (2020/09/21)
The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1cat-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.
Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: Structure-based drug design, synthesis, and biological evaluation
Vernier, William,Chong, Wesley,Rewolinski, David,Greasley, Samantha,Pauly, Thomas,Shaw, Morena,Dinh, Dac,Ferre, Rose Ann,Nukui, Seiji,Ornelas, Martha,Reyner, Eric
experimental part, p. 3307 - 3319 (2010/07/10)
A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.
IL-8 RECEPTOR ANTAGONISTS
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Page/Page column 47, (2008/12/06)
This invention relates to novel compounds, compositions and combinations thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
