Poster Presentation RACI Biomolecular Division Conference 2013

Quinazoline Sulfonamides as Dual Binders of the Proteins Bcl-2 and Bcl-xL with Potent Pro-apoptotic Cell-Based Activity (#89)

Brad E Sleebs 1 2 , Peter E Czabotar 1 2 , Wayne J Fairbrother 3 , Douglas W Fairlie 1 2 , John A Flygare , David CS Huang 1 2 , Wilhelmus JA Kersten 1 2 , Micheal FT Koehler 3 , Guillaume Lessene 1 2 , Kym Lowes 1 2 , John P Parisot 1 2 , Brian J Smith 1 2 , Morey L Smith 4 , Andrew J Souers 4 , Ian P Street 1 2 , Hong Yang 1 2 , Jonathan B Baell 1 2
  1. The Walter and Eliza Hall Institute, Parkville, Victoria, Australia
  2. The University of Melbourne, Parkville, Victoria, Australia
  3. Genentech, South San Francisco, California, United States
  4. Abbott Laboratories, Abbott Park, Illinois, United States

Apoptosis is the hallmark of cell death. A key component of cell death is the interplay between pro-apoptotic (bad, bim, bik, bmf, noxa) and anti-apoptotic proteins (Bcl-xL, Bcl-2, Bcl-w, Mcl-1, A1). In many cancerous cells anti-apoptotic proteins are over expressed preventing cell death. Small-molecule mimetics of BH3-only proteins neutralize the pro-survival proteins present, allowing the release of Bax/Bak and ensuing apoptosis via p53 activation.

BH3 mimetics such as, ABT-7371 and ABT-263,2 are both potent inhibitors of the BH3 anti-apoptotic proteins, Bcl-w, Bcl-xL and Bcl-2. A feature of these drugs is the presence of an acylsulfonamide moiety which represents a potential metabolic liability. To overcome this potential liability, a series of novel quinazoline sulfonamides were designed and synthesized that contain a heterocyclic alternative to the acylsulfonamide.

The quinazoline sulfonamides exhibit low nanomolar affinities for Bcl-2 and Bcl-xL, and no affinity for Mcl-1, however differ from ABT-263 and ABT-737 in that they have reduced affinity for Bcl-w. X-ray crystallographic analysis of a quinazoline in complex with Bcl-xL, suggests a possible hypothesis for this difference. The quinazolines demonstrate potent and mechanism-based activity in a MEF cell line where Mcl-1 has been genetically deleted. They also exhibit submicromolar activity against a panel of small-cell lung carcinoma cell lines in the presence of 10% human serum.3

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  1. Oltersdorf, T.; et al. Nature 2005, 435, 677–681.
  2. Park, C.M.; et al. J. Med. Chem. 2008, 51, 6902–6915.
  3. Sleebs, B.E.; et al. J. Med. Chem. 2011, 54, 1914–1926.