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
  • 1. Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: [email protected].
  • 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.