- De-novo designed library of benzoylureas as inhibitors of BCL-X L: Synthesis, structural and biochemical characterization
-
The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 μM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.
- Brady, Ryan M.,Vom, Amelia,Roy, Michael J.,Toovey, Nathan,Smith, Brian J.,Moss, Rebecca M.,Hatzis, Effie,Huang, David C. S.,Parisot, John P.,Yang, Hong,Street, Ian P.,Colman, Peter M.,Czabotar, Peter E.,Baell, Jonathan B.,Lessene, Guillaume
-
p. 1323 - 1343
(2014/03/21)
-
- NEW COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
-
This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1) wherein R1, R2, R4, R6, E, n, Y1, Y2, Y3, Y4, Y5, L, B, R8, and m are as defined in the claims.
- -
-
Page/Page column 100-101
(2012/06/30)
-
- INFLUENCE OF THE ANGULAR LINKAGE ON THE MESOMORPHIC PROPERTIES OF CHOLESTERYL ARYLBENZOATES.
-
Some cholesteryl esters of arylbenzoic acids incorporating angular linkage such as -Co-, -O-, -S-, and -CH//2-, were prepared, and the transition temperatures and heats determined. The cholesteric-isotropic transition temperatures are likely to correlate with the angular correlation parameters of these carboxylic acid moieties. The mesomorphic phenomena are discussed in terms of the molecular structure and electronic effect of these linkages.
- Koden,Takenaka,Kusabayashi
-
p. 137 - 150
(2007/10/02)
-