Cells utilize multiple systems to maintain homeostasis. In healthy cells, these systems function normally however, cancer cells can hijack these systems to promote tumor growth. One system that is targeted is the intrinsic apoptosis pathway which is regulated by the B-cell lymphoma 2 (BCL-2) family of proteins. This family is comprised of pro-apoptotic proteins, which include BAK and BAX, and anti-apoptotic proteins, such as BCL-2, BCL-xL, and MCL-1. Inside a healthy cell, these proteins sequester each other preventing cell death. This interaction occurs on the BH3 binding groove found on the surface of anti-apoptotic proteins. Each BH3 groove interacts by recognizing the complementary BH3 “death” domain on pro-apoptotic proteins. A feature of this “death” domain is that it changes into an a-helix structure once bound. This balance is disrupted when a stress is detected, and the cell upregulates pro-apoptotic proteins in response and activation of BAK and BAX causes apoptosis. Cancer cells hijack this system by upregulating anti-apoptotic proteins to such a heightened level that all pro-apoptotic proteins are sequestered, and tumorigenesis occurs. Multiple inhibitors have been designed to target anti-apoptotic proteins via the BH3 binding groove. These have been dubbed “BH3 mimetics”, and they all seek to hoodwink the anti-apoptotic proteins into binding which releases pro-apoptotic proteins causing apoptosis. The only FDA-approved BH3 mimetic is venetoclax, which selectively binds the BCL-2 protein. Additionally, there are multiple clinical trials ongoing for inhibitors that target BCL-xL and MCL-1. Contrarily, BFL-1 is an anti-apoptotic protein that has received less attention, and there are no BFL-1 small-molecule inhibitors. BFL-1 is commonly overexpressed in leukemias, lymphomas, and melanomas while also being recently implicated in venetoclax resistance in leukemias. Unique to BFL-1 is a cysteine residue (Cys55) in its BH3-binding groove, and this residue may be covalently captured in drug design. Here, we will capitalize on previously validated BH3 a-helix mimetic scaffolds and employ computer-aided drug design (CADD) to (i) direct the modification of these scaffolds towards the discovery of selective inhibitors for BFL-1 through non-covalent interactions, as well as (ii) equip our inhibitors with irreversible and reversible covalent electrophilic warheads to react with Cys55. Our efforts towards this goal will be presented.

Synthesizing a-helix mimetics with CADD-positioned electrophilic warheads to inhibit the BFL-1 anti-apoptotic protein

ACS Spring 2022

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