Precision Targeting of BFL-1/A1 and an ATM Co-dependency in Human Cancer

Abstract

SUMMARY Cancer cells overexpress a diversity of anti-apoptotic BCL-2 family proteins, such as BCL-2, MCL-1, and BFL-1/A1, to enforce cellular immortality. Thus, intensive drug development efforts have focused on targeting this class of oncogenic proteins to overcome treatment resistance. Whereas a selective BCL-2 inhibitor has been FDA approved and several small molecule inhibitors of MCL-1 have recently entered phase I clinical testing, BFL-1/A1 remains undrugged. Here, we developed a series of stapled peptide design principles to engineer a functionally selective and cell-permeable BFL-1/A1 inhibitor that is specifically cytotoxic to BFL-1/A1-dependent human cancer cells. Because cancers harbor a diversity of resistance mechanisms and typically require multi-agent treatment, we further investigated BFL-1/A1 co-dependencies by mining a genome-scale CRISPR-Cas9 screen. We identified ataxia-telangiectasia-mutated (ATM) kinase as a BFL-1/A1 co-dependency in acute myeloid leukemia (AML), which informed the validation of BFL-1/A1 and ATM inhibitor co-treatment as a synergistic approach to subverting apoptotic resistance in cancer.

BFL1 modulates apoptosis at the membrane level through a bifunctional and multimodal mechanism showing key differences with BCLXL

“…BFL1 is an apoptosis-regulatory protein of the BCL2 family that has recently emerged as an important factor for oncogenesis and resistance to chemotherapy [16–23], akin to other BCL2-type proteins [24]. However, the mechanistic details of BFL1 action are much less well understood compared to those of BCL2, BCLXL, and MCL1.…”

“…BFL1 is one of the least extensively studied BCL2-type proteins [16, 17]. It is accepted that BFL1 prevents apoptosis under specific physiological settings, and that BFL1 contributes to tumour progression and drug resistance in selected types of human cancer [16–23], akin to BCL2, BCLXL and MCL1 [24]. However, the precise mode of action of BFL1 is less well understood than those of BCL2, BCLXL and MCL1.…”

Selective Covalent Targeting of Anti‐apoptotic BFL‐1 by a Sulfonium‐Tethered Peptide

“…BFL‐1 is a BCL‐2 family protein overexpressed in various cancers, including melanoma, lymphoma and CLL [22–25] . In melanoma, BFL‐1 is over expressed and regulated by NFkB and the proteasome, [23] which correlates with chemoresistance and metastasis [26] .…”

Recognition of ASF1 by Using Hydrocarbon‐Constrained Peptides

“…In the context of α‐helix‐mediated PPIs, considerable effort has been exerted on developing methods for constraining (or “stapling”) peptides in an α‐helical conformation. This approach has been used to confer enhanced proteolytic stability, enhanced cell‐uptake and, in some cases, enhanced target affinity on constrained peptide sequences . We recently introduced a series of reagents and approaches for constraining peptides in a helical conformation .…”