153398-67-5Relevant academic research and scientific papers
Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis
Thomas, Michael,Brand, Stephen,De Rycker, Manu,Zuccotto, Fabio,Lukac, Iva,Dodd, Peter G.,Ko, Eun-Jung,Manthri, Sujatha,McGonagle, Kate,Osuna-Cabello, Maria,Riley, Jennifer,Pont, Caterina,Simeons, Frederick,Stojanovski, Laste,Thomas, John,Thompson, Stephen,Viayna, Elisabet,Fiandor, Jose M.,Martin, Julio,Wyatt, Paul G.,Miles, Timothy J.,Read, Kevin D.,Marco, Maria,Gilbert, Ian H.
, p. 5905 - 5930 (2021)
There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.
2-AMINOIMIDAZOLE-PHENYL DERIVATIVES USEFUL FOR CONTROLLING MICROBIAL GROWTH
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Page/Page column 38-39, (2018/10/19)
Provided are 2-aminoimidazole-phenyl derivative compounds of Formula (I): which compounds are useful in methods of controlling microbial growth, such as by enhancing the effects of an antibiotic administered in combination with the compound. Compositions
Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors
Andreani, Aldo,Granaiola, Massimiliano,Leoni, Alberto,Locatelli, Alessandra,Morigi, Rita,Rambaldi, Mirella,Varoli, Lucilla,Lannigan, Deborah,Smith, Jeff,Scudiero, Dominic,Kondapaka, Sudhir,Shoemaker, Robert H.
experimental part, p. 4311 - 4323 (2011/11/12)
The activity of a series of imidazo[2,1-b]thiazole guanylhydrazones as inhibitors of p90 ribosomal S6 kinase 2 (RSK2) is described. It was found that a small subset of compounds show both potent inhibition of RSK2 kinase activity and tumor cell growth in vitro. Detailed study of one of the most active compounds indicates a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases. Selective inhibition of the MCF-7 breast tumor cell line compared to MCF-10A non-transformed cells, as well as selective inhibition of the biomarker GSK3 provides evidence that the compounds can affect the RSK2 target in cells.
