2. Academic Validation
  3. S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth

S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth

  • Oncotarget. 2018 Apr 13;9(28):20075-20088. doi: 10.18632/oncotarget.24744.
Patrick Casara  # 1,  James Davidson  # 2,  Audrey Claperon  # 3,  Gaëtane Le Toumelin-Braizat 3,  Meike Vogler 4,  Alain Bruno 5,  Maïa Chanrion 3,  Gaëlle Lysiak-Auvity 3,  Thierry Le Diguarher 1,  Jérôme-Benoît Starck 1,  Ijen Chen 2,  Neil Whitehead 2,  Christopher Graham 2,  Natalia Matassova 2,  Pawel Dokurno 2,  Christopher Pedder 2,  Youzhen Wang 6,  Shumei Qiu 6,  Anne-Marie Girard 3,  Emilie Schneider 3,  Fabienne Gravé 3,  Aurélie Studeny 3,  Ghislaine Guasconi 3,  Francesca Rocchetti 3,  Sophie Maïga 7,  Jean-Michel Henlin 1,  Frédéric Colland 3,  Laurence Kraus-Berthier 5,  Steven Le Gouill 7,  Martin J S Dyer 8,  Roderick Hubbard 2,  Mike Wood 2,  Martine Amiot 7,  Gerald M Cohen 9,  John A Hickman 3,  Erick Morris 6,  James Murray 2,  Olivier Geneste 3
Affiliations

Affiliations

  • 1 Institut de Recherches Servier Discovery Chemistry Unit, Croissy Sur Seine, France.
  • 2 Vernalis (R&D) Ltd., Cambridge, UK.
  • 3 Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine, France.
  • 4 Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt, Germany.
  • 5 Institut de Recherches Internationales Servier, Oncology R&D Unit, Suresnes, France.
  • 6 Novartis Institute of Biomedical Research, Oncology Drug Discovery, Cambridge, MA, USA.
  • 7 CRCINA, INSERM, CNRS, Université de Nantes, CHU de Nantes, Nantes, France.
  • 8 Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.
  • 9 Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
  • # Contributed equally.
PMID: 29732004 DOI: 10.18632/oncotarget.24744
Abstract

Escape from Apoptosis is one of the major hallmarks of Cancer cells. The B-cell Lymphoma 2 (Bcl-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member Bcl-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, Bcl-2 has become an attractive target for therapeutic strategy in Cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable Bcl-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of Bcl-2. Its selectivity profile demonstrates no significant binding to Mcl-1, Bfl-1 (BCL2A1/A1) and poor affinity for Bcl-xL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of Apoptosis including externalization of phosphatidylserine, Caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces Apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the Bcl-2 protein.

Keywords

BCL-2; BH3-mimetics; apoptosis; hematological malignancies; inhibitor.

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