Session: Posters:

One of the deadliest traits of cancer cells is their ability to hijack existing apoptotic pathways in order to promote tumorigenesis. Of particular notoriety is the Bcl-2 family of proteins, which comprises pro- and anti-apoptotic members that are tightly regulated to balance cell survival and cell death. Within the Bcl-2 pathway, cancer cells upregulate the anti-apoptotic proteins in order to evade cell death. Bcl-2, Bcl-xL, and Mcl-1 are infamous examples of these upregulated proteins. Indeed, intense research has centered around the discovery of inhibitors of these proteins by mimicking the BH3 a-helical domains of their counterpart proteins, such as Bak and Bim. In contrast, the sister anti-apoptotic protein Bfl-1 has received less attention. The selective inhibition of specific anti-apoptotic Bcl-2 proteins has proven a considerable – but not insurmountable – challenge owing to highly conserved BH3-binding domains. Bfl-1 is unique in that it presents a cysteine residue (Cys55) within the p1 sub-pocket of the BH3-binding groove that may be exploited in drug design, accelerating the discovery of selective Bfl-1 inhibitors. Therefore, towards a novel class of small-molecule Bfl-1 inhibitors, we are leveraging findings from our previously reported dual Bcl-xL/Mcl-1 inhibitor JY-1-106, which was designed to mimic the BH3 a-helix. As guided by molecular modeling, we will capitalize on Bfl-1’s unusual surface cysteine to garner selectivity for this family member. Particularly, Michael acceptor motifs will be engineered into the synthetic a-helix mimetics in those regions that are predicted to bind close to Cys55, promoting permanent capture of the ligands and irreversible inhibition of the Bfl-1 protein. Our progress towards this goal will be presented.

Mr. Christopher Craig Goodis

Graduate Research Assistant, University of Maryland, Baltimore

Appearances