2. Academic Validation
  3. Towards the next generation of dual Bcl-2/Bcl-xL inhibitors

Towards the next generation of dual Bcl-2/Bcl-xL inhibitors

  • Bioorg Med Chem Lett. 2014 Jul 15;24(14):3026-33. doi: 10.1016/j.bmcl.2014.05.036.
Jeffrey G Varnes 1,  Thomas Gero 2,  Shan Huang 2,  R Bruce Diebold 2,  Claude Ogoe 2,  Paul T Grover 2,  Mei Su 2,  Prasenjit Mukherjee 2,  Jamal Carlos Saeh 2,  Terry MacIntyre 2,  Galina Repik 2,  Keith Dillman 2,  Kate Byth 2,  Daniel John Russell 2,  Stephanos Ioannidis 2
Affiliations

Affiliations

  • 1 Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: Jeffrey.Varnes@Astrazeneca.com.
  • 2 Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
PMID: 24881567 DOI: 10.1016/j.bmcl.2014.05.036
Abstract

Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.

Keywords

Apoptosis; B-cell lymphoma; Bcl-2; Bcl-x(L); Navitoclax.

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