477940-63-9Relevant academic research and scientific papers
Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XLand BCL-2
Roy, Michael J.,Vom, Amelia,Okamoto, Toru,Smith, Brian J.,Birkinshaw, Richard W.,Yang, Hong,Abdo, Houda,White, Christine. A.,Segal, David,Huang, David C. S.,Baell, Jonathan B.,Colman, Peter M.,Czabotar, Peter E.,Lessene, Guillaume
, p. 5447 - 5469 (2021)
The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5"pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.
PEPTIDIC COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
-
Page 85, (2010/11/30)
The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
