Solid-phase synthesis and screening of N-acylated polyamine (NAPA) combinatorial libraries for protein binding.

Inhibitors for protein-protein interactions are challenging to design, in part due to the unique and complex architectures of each protein's interaction domain. Most approaches to develop inhibitors for these interactions rely on rational design, which requires prior structural knowledge of the target and its ligands. In the absence of structural information, a combinatorial approach may be the best alternative to finding inhibitors of a protein-protein interaction.

N-acylpolyamine inhibitors of HDM2 and HDMX binding to p53.

Selective inhibition of protein-protein interactions important for cellular processes could lead to the development of new therapies against disease. In the area of cancer, overexpression of the proteins human double minute 2 (HDM2) and its homolog HDMX has been linked to tumor aggressiveness. Both HDM2 and HDMX bind to p53 and prevent cell cycle arrest or apoptosis in damaged cells.

Induction of apoptosis promoted by Bang52; a small molecule that downregulates Bcl-x(L).

Cancer cells evade death by over-producing specific proteins that inhibit apoptosis. One such group of proteins is the Bcl-2 family, of which Bcl-x(L) is an important member. This protein binds and inhibits BAK, another protein that promotes apoptosis.

A new family of small molecules to probe the reactivation of mutant p53.

Cells that express mutant p53 derived from cancers are selectively killed by a new class of small organic molecules. The protein p53 is recognized as one of the most important guardians in the body that prevents tumor development. Mutant forms of p53 are present in approximately 50% of all human cancers.