Structure-Based Discovery of Potent BCL-XL Inhibitors through Rescaffolding

Evasion of apoptosis is a hallmark of cancer. Deregulation of BCL-XL, a member of the BCL-2 family of proteins, has been linked to the development of various tumor types. This study presents the design and synthesis of BCL-XL inhibitors with novel mono- and bicyclic cores. The new structural features were optimized to combine high binding efficiency with the opening of diverse novel vectors for additional modifications. The lead compounds exhibited picomolar affinities and significant cellular potency in the BCL-XL-dependent MOLT-4 cell line, which also translated into marked tumor growth inhibition in a xenograft study. These findings highlight the potential of BCL-XL inhibitors as therapeutic agents in cancer treatment by targeting the apoptotic intrinsic pathway.

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Journal
Journal of Medicinal Chemistry
Published
2026-06-12
DOI
https://doi.org/10.1021/acs.jmedchem.6c00865
Primary Topic
Cell death mechanisms and regulation
Type
article
Field-Weighted Citation Impact
0.00

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article

Structure-Based Discovery of Potent BCL-XL Inhibitors through Rescaffolding

Gaëtane Le Toumelin-Braizat, Frédéric Colland, Didier Demarles, András Kotschy et al.
Journal of Medicinal Chemistry
Cell death mechanisms and regulation
article

Structure-Based Discovery of Potent BCL-XL Inhibitors through Rescaffolding

Gaëtane Le Toumelin-Braizat, Frédéric Colland, Didier Demarles, András Kotschy, Laura Bresson, Simon T. Bedford, Zoltán Madarász, Miklós Nyerges, Julia Smith, James Davidson, Francesca Rocchetti, P. Dokurno, James B. Murray, Roderick E. Hubbard, Jérôme-Benoît Starck, Attila Paczal, Márk Molnár, Paul Webb, Olivier Geneste, Emma Sanders, Neil Whitehead, Teresa Brooks, Ana Leticia Maragno, Zoe Daniels, Mark Dodsworth, Tibor Novak, Matyas Pal Timari, Andras Herner, Rachel Parsons
article en

Abstract

Evasion of apoptosis is a hallmark of cancer. Deregulation of BCL-XL, a member of the BCL-2 family of proteins, has been linked to the development of various tumor types. This study presents the design and synthesis of BCL-XL inhibitors with novel mono- and bicyclic cores. The new structural features were optimized to combine high binding efficiency with the opening of diverse novel vectors for additional modifications. The lead compounds exhibited picomolar affinities and significant cellular potency in the BCL-XL-dependent MOLT-4 cell line, which also translated into marked tumor growth inhibition in a xenograft study. These findings highlight the potential of BCL-XL inhibitors as therapeutic agents in cancer treatment by targeting the apoptotic intrinsic pathway.

Journal of Medicinal Chemistry
Eötvös Loránd University (HU), Laboratoire Francis Perrin (FR), Granta Design (United Kingdom) (GB)
Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
Good health and well-being
Openalex Percentile: Top 10%
Cell death mechanisms and regulation
DOIOpen Access PDFOpenAlex
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