Structural insights into chemoresistance mutants of BCL-2 and their targeting by stapled BAD BH3 helices

Thomas M. DeAngelo, Utsarga Adhikary, Kyle J. Korshavn, Hyuk-Soo Seo, Clara R. Brotzen-Smith, Christina M. Camara, Sirano Dhe-Paganon, Gregory H. Bird, Thomas E. Wales and Loren D. Walensky ()
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Thomas M. DeAngelo: Dana-Farber Cancer Institute
Utsarga Adhikary: Dana-Farber Cancer Institute
Kyle J. Korshavn: Dana-Farber Cancer Institute
Hyuk-Soo Seo: Dana-Farber Cancer Institute
Clara R. Brotzen-Smith: Dana-Farber Cancer Institute
Christina M. Camara: Dana-Farber Cancer Institute
Sirano Dhe-Paganon: Dana-Farber Cancer Institute
Gregory H. Bird: Dana-Farber Cancer Institute
Thomas E. Wales: Northeastern University
Loren D. Walensky: Dana-Farber Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract BCL-2 is a central regulator of apoptosis and inhibits cell death by sequestering pro-apoptotic BH3 alpha-helices within a hydrophobic surface groove. While venetoclax, a BH3-mimetic drug, has transformed the treatment of BCL-2–driven malignancies, its efficacy is increasingly limited by acquired resistance mutations that disrupt small-molecule binding yet preserve anti-apoptotic function—reflecting a remarkable structural adaptation. Here, we employ hydrocarbon-stapled alpha-helices derived from the BAD BH3 motif as conformation-sensitive molecular probes to investigate this therapeutic challenge. The stapled peptides not only retain high-affinity binding to all BCL-2 variants but also show enhanced potency to select venetoclax-resistant mutants. Structural analyses, including X-ray crystallography and hydrogen-deuterium exchange mass spectrometry (HDX MS), demonstrate that these stapled helices restore native BH3 engagement by reversing the conformational consequences of resistance mutations. Notably, we identify a serendipitous interaction between the α3–α4 region of BCL-2 and hydrocarbon staple, which further compensates for altered groove conformation and contributes to mutant binding affinity. Together, these findings offer mechanistic insights into BCL-2 drug resistance and reveal a blueprint for designing next-generation inhibitors that overcome this clinically significant barrier to durable treatment responses.

Date: 2025
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DOI: 10.1038/s41467-025-63657-y

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