A key hallmark of cancer is the ability to manipulate homeostatic pathways within cells. A major example of this is the B-cell lymphoma 2 (BCL-2) protein mediated intrinsic apoptotic pathway. The BCL-2 protein family comprises anti-apoptotic proteins (e.g. BCL-2, MCL-1 and BCL-xL) and pro-apoptotic proteins, divided into BH3-only proteins, e.g. PUMA, and the “effectors” BAK and BAX. Under normal conditions, these proteins exist in similar ratios, interacting with one another via a conserved binding groove on the surface of anti-apoptotic proteins. This groove recognizes the α-helix BH3 “death” domain of pro-apoptotic proteins. Under these conditions, the pro-apoptotic proteins are sequestered, and apoptosis is abrogated. However, when stress occurs in the cell, pro-apoptotic proteins are upregulated, displacing effectors from their anti-apoptotic counterparts, committing the cells to apoptosis. In cancer cells, this is reversed, and anti-apoptotic proteins are overproduced such that all pro-apoptotic proteins are bound, disabling their ability to induce apoptosis. Inhibitors seeking to restore apoptotic function are designed to target the BH3 binding groove by mimicking the BH3 “death” domain. These so-called “BH3 mimetics” dupe the anti-apoptotic proteins, becoming themselves bound and releasing sequestered pro-apoptotic proteins, which restores apoptosis in cancerous cells. Currently, the only FDA approved BH3 mimetic is venetoclax which selectively binds to the BCL-2 protein. Additionally, multiple clinical trials are ongoing for inhibitors that target MCL-1, BCL-xL and dual inhibitors which are also being explored. BFL-1 is an anti-apoptotic protein that has received less attention than its sister proteins. BFL-1 is overexpressed in a variety of melanomas, leukemias, and melanomas and plays a role in venetoclax resistance in certain leukemias. In contrast to the other BCL-2 proteins, BFL-1 presents a solvent-exposed cysteine (Cys55) on the wall of the BH3-binding groove and an aspartate (Asp78) near the middle of the groove. Towards the discovery of new BFL-1 inhibitors, we employed computer-aided drug design/virtual screening that yielded ligands targeting Cys55 and/or Asp78. A variety of these hit compounds spanning a range of chemotypes were subsequently purchased or synthesized, and our findings will be presented. Additionally, we screened an in-house library of synthetic BH3 α-helix mimetics, whose activities against BFL-1 will also be disclosed.

Discovery of novel BFL-1 inhibitors by computer-aided drug design and screening an in-house library of synthetic BH3 α-helix mimetics

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.