- Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis
-
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.
- 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.
-
supporting information
p. 5905 - 5930
(2021/06/01)
-
- This new pharmaceutical use (6-1, 6-dihydro-2-yl) amide derivative, as the inhibitor of this preparation and AKT (PKB) phosphoenzyme
-
The invention relates to the novel materials of formula (I), wherein each of the substituents R, R1, R2, R3, R4 and R5 is as defined herein. The materials are useful as inhibitors of AKT(PKB) phosphorylation.
- -
-
-
- FORMULATION OF QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
-
The present invention relates to a composition comprising an inclusion complex of a cyclodextrin and quinazoline containing zinc-binding moiety based derivatives. The cyclodextrin is preferable a β-cyclodextrin or a derivative thereof. The quinazolines have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
- -
-
-
- TARTRATE SALTS OF QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
-
The present invention relates to tartrate salts of quinazoline containing zinc-binding moiety based derivatives that are inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The tartrate salts may further act as HDAC inhibitors.
- -
-
Page/Page column 78
(2009/04/24)
-
- MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
-
The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.
- -
-
Page/Page column 139
(2008/06/13)
-
- Facile Synthesis of Ethynylated Benzoic Acid Derivatives and Aromatic Compounds via Ethynyltrimethylsilane
-
The coupling reaction between an aromatic halide and ethynyltrimethylsilane under the catalysis of palladium(0) generated in situ, followed by treatment of the (trimethylsilyl)ethynyl product with potassium carbonate in methanol at ambient temperatures, provides a simple approach to various ethynylated benzoic acid derivatives and other aromatic compounds.The conditions for the removal of the trimethylsilyl group were very mild, so that base-sensitive functionalities on the aromatic moiety could be tolerated.
- Austin, William B.,Bilow, Norman,Kelleghan, William J.,Lau, Kreisler S. Y.
-
p. 2280 - 2286
(2007/10/02)
-