Poster Presentation RACI Biomolecular Division Conference 2013

Structure-based design of a-helical mimetic inhibitors of pro‑survival Bcl-2 proteins (#99)

Amelia Vom 1 , Michael Roy 1 , Soo-San Wan 1 , Brian Smith 2 , Peter Czabotar 3 , Guillaume Lessene 1
  1. Walter and Elizer Hall Institute, Bundoora, Vic, Australia
  2. La Trobe University, Bundoora, Victoria, Australia
  3. Walter and Elizer Hall Institute, Parkville, Victoria, Australia

Alteration of programmed cell death response due to over-expression of pro-survival proteins such as Bcl‑xL, Bcl-2, and Mcl-1 or down-regulation of pro-apoptotic BH3-only proteins is a key driver in cancer initiation, progression and of resistance to chemotherapy. Notably, most anti‑cancer drugs depend on a functional apoptotic machinery to elicit their activity. Thus, restoring the proper unraveling of Bcl-2 family-driven apoptosis by mimicking the activity of the BH3-only proteins with small molecules provides a potential strategy for the development of anticancer therapies.

We employed a structure-based approach to design novel peptidomimetics of the BH3-only proteins targeting the pro-survival protein Bcl-xL. Our design was guided by the X-ray structure of the Bim/Bcl-xL complex, which reveals that the Bim-BH3 peptide adopts a helical conformation, and projects four hydrophobic residues on one face of the α-helix into four corresponding hydrophobic pockets located within the binding cleft of Bcl-xL. Our molecular scaffold uses a benzoylurea core functionalised tomimic three hydrophobic side chains of the Bim-BH3 peptide. We demonstrate how our highly modular synthesis enables an extensive Structure-Activity Relationship (SAR) study affording benzoylureas with nanomolar affinity for Bcl-xL. Investigations into the SAR of the series and the underpinning chemistry will be presented, and the critical structural data obtained via X-ray crystallography and the computational techniques used to design the benzoylurea peptidomimetics will be discussed. Overall, our work affords a unique series of validated inhibitors of the Bcl-2 family of proteins.

1116-raci%202.jpg