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

  • J Med Chem. 2026 Jun 25;69(12):14804-14818. doi: 10.1021/acs.jmedchem.6c00865.
Matyas Pal Timari  1  2 ,  Attila Paczal  1 ,  Andras Herner  1 ,  Mark Molnar  1 ,  Zoltan Madarasz  1 ,  Miklos Nyerges  1 ,  Simon T Bedford  3 ,  Teresa Brooks  3 ,  James Davidson  3 ,  Zoe Daniels  3 ,  Mark Dodsworth  3 ,  Pawel Dokurno  3 ,  James B Murray  3 ,  Rachel Parsons  3 ,  Emma Sanders  3 ,  Julia Smith  3 ,  Paul Webb  3 ,  Neil Whitehead  3 ,  Roderick E Hubbard  3 ,  Jérôme-Benoît Starck  4 ,  Ana Leticia Maragno  4 ,  Gaëtane Le Toumelin-Braizat  4 ,  Laura Bresson  4 ,  Francesca Rocchetti  4 ,  Didier Demarles  4 ,  Frédéric Colland  4 ,  Olivier Geneste  4 ,  Andras Kotschy  1 ,  Tibor Novak  1
Affiliations
  • 1. Servier Research Institute of Medicinal Chemistry, Záhony utca 7, Budapest H-1031, Hungary.
  • 2. Hevesy György PhD School of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary.
  • 3. Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, U.K.
  • 4. Institut de Recherche Servier, 22 route 128/rue Francis Perrin, Gif-sur-Yvette 91190, France.
PMID: 42283755 DOI: 10.1021/acs.jmedchem.6c00865
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.

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