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Targeting BFL-1 Reactivates Cancer Cell Death

BFL-1 inhibitors represent potential first-in-class compounds designed to reactivate apoptosis, or cell death, in multiple cancer subtypes.

  • Therapeutics

Project Overview

  • BFL-1 is a protein that inhibits cell death and is implicated in the progression of several cancers, including leukemia, lymphoma, melanoma, breast, liver and other cancers. BFL-1 also plays a role in the development of resistance to specific cancer treatments. Despite the potential impact of targeting BFL-1, no inhibitors are available.
  • Dana-Farber researchers have created the first known selective BFL-1 inhibitors.
  • The technology to develop, screen, and validate BFL-1 inhibitors is also available for sponsored research or licensing agreements.

Technology

BCL-2 family proteins are key regulators of apoptosis, an essential form of programmed cell death. Some members of the family, like BCL-2, MCL-1, and BFL-1, act as guardians against cell death, while others execute apoptosis. Understanding how these proteins work together is vital for creating new treatments that can either activate or inhibit cell death in diseases of too many or too few cells, respectively.

One therapeutic strategy involves the use of inhibitors that target BCL-2 proteins to trigger cell death in cancer cells. Venetoclax, the pioneering drug in this category approved by the FDA, specifically inhibits the BCL-2 protein and has shown significant efficacy in treating chronic lymphocytic leukemia (CLL). It is now commercially very successful and has become a standard part of treatment for a variety of hematologic cancers. Nevertheless, resistance to venetoclax has been observed in some patients.

A Dana-Farber research team, led by Loren Walensky, MD, PhD, has pioneered several innovative methods for studying and targeting the broad spectrum of BCL-2 family proteins. These methods are instrumental in designing drugs that selectively influence cell death in both cancer and other diseases.

Their research has particularly focused on BFL-1, a member of the BCL-2 family that inhibits cell death and is associated with a range of cancers, including leukemia, lymphoma, melanoma, and other solid tumors.

Targeting BFL-1 is critical, as BFL-1-compounds could address a lack of response to venetoclax or to emerging MCL-1 inhibitors that are in clinical trials (although MCL-1’s role in normal cells may limit their therapeutic window). BFL-1 is known to play a role in the development of resistance to venetoclax. The Dana-Farber team has identified a series of selective inhibitors that target BFL-1, which had been considered undruggable, with the goal of reactivating apoptosis in cancers driven by this protein.

In their 2016 and 2018 publications in Cell Chemical Biology, Walensky and his colleagues reported the discovery of the first selective BFL-1 inhibitors. These breakthroughs were made possible by identifying a unique cysteine residue (C55) within BFL-1’s critical BH3-binding groove, which can be targeted by cysteine-reactive compounds.

Building on this discovery, the team has amassed extensive expertise on BFL-1, which they leveraged during the initial stages of drug development, including the hit-to-lead and lead optimization phases. They have developed a robust array of screening and pharmacodynamic assays to facilitate these efforts. These tools provide blueprints for the development of selective drugs that can alter cell death pathways in cancer.

The team is looking for partners to leverage these tools to create clinical-grade inhibitors that target BFL-1, with the potential to become new treatments for cancer.

Team Members: Loren Walensky, MD, PhD, Gregory Bird, PhD, Annissa Huhn, PhD

Applications

The team proposes to develop and validate BFL-1 stapled peptide and small-molecule inhibitors for clinical development using previously established successful clinical path strategies for venetoclax.

BFL-1 monotherapy could be effective in cancers that are highly dependent on BFL-1 for survival, including leukemias, lymphomas, and melanomas. Data in the literature also support

the development of selective BFL-1 inhibitors for other solid tumors, including meningioma, hepatocellular carcinoma, and breast cancer.

In addition, BFL-1 inhibition may be used in combination with other treatments to sensitize apoptosis, similar to how venetoclax is presently being used in various combinations. Selective BFL-1 inhibitors may also be useful in certain types of chemotherapy resistance including fludarabine-resistant CLL, venetoclax-resistant acute myeloid leukemia (AML), chemoresistant multiple myeloma, and BRAF inhibitor-resistant melanoma.

Interested in learning more?

Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors

Cell Chemical Biology paper

Restoring Apoptosis by Selective Inhibition of BFL-1 as a Cancer Therapeutic Strategy

INPART technology summary

Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering

Cell Chemical Biology paper

Opportunities

Dana-Farber is interested in sponsored research or licensing opportunities supporting the selective BFL-1 inhibitor development program.

Get in touch

Team Members