ArticleCell chemical biology2020
Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.
Article in Cell chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 37 citations in OpenAlex.
- Targeting protein-protein interactions in the BCL-2 family: opportunities for precision oncology.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Covalent inhibition of pro-apoptotic BAX.Nature chemical biology · 2024Article
- Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.ACS medicinal chemistry letters · 2024Article
- Proteomic discovery of chemical probes that perturb protein complexes in human cells.Molecular cell · 2023Article
- Targeting regulated cell death pathways in acute myeloid leukemia.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Phytochemical Screening and Bioactivity Studies of Endophytes Cladosporium sp. Isolated from the Endangered Plant Vateria Indica Using In Silico and In Vitro Analysis.Applied biochemistry and biotechnology · 2022Article
- Last but not least: BFL-1 as an emerging target for anti-cancer therapies.Biochemical Society transactions · 2022Review
- Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex.Journal of the American Chemical Society · 2022Article
- Recent applications of covalent chemistries in protein-protein interaction inhibitors.RSC medicinal chemistry · 2022Review
- The role of BCL-2 family proteins in regulating apoptosis and cancer therapy.Frontiers in oncology · 2022Review
- Article
- Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas.Blood · 2021Article
- Visualizing and trapping transient oligomers in amyloid assembly pathways.Biophysical chemistry · 2021Review
- A redox switch regulates the structure and function of anti-apoptotic BFL-1.Nature structural & molecular biology · 2020Article
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.