21802-84-6Relevant academic research and scientific papers
Anticancer ruthenium complexes with HDAC isoform selectivity
Blower, Tim R.,Cross, Jasmine M.,Kingdon, Alexander D. H.,Pal, Robert,Picton, David M.,Walton, James W.
supporting information, (2020/05/29)
The histone deacetylase (HDAC) enzymes have emerged as an important class of molecular targets in cancer therapy, with five inhibitors in clinical use. Recently, it has been shown that a lack of selectivity between the 11 Zn-dependent HDAC isoforms may lead to unwanted side-effects. In this paper, we show that piano stool Ru complexes can act as HDAC inhibitors, and variation in the capping arene leads to differences in HDAC isoform selectivity.
An NMR-guided screening method for selective fragment docking and synthesis of a warhead inhibitor
Khattri, Ram B.,Morris, Daniel L.,Davis, Caroline M.,Bilinovich, Stephanie M.,Caras, Andrew J.,Panzner, Matthew J.,Debord, Michael A.,Leeper, Thomas C.
supporting information, (2016/07/29)
Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and 15N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins-a heretofore untapped reservoir for antibiotic agents.
