Identification Of A Non-Canonical Bh3 Peptide That Binds The Bh3 Pocket Of Mcl-1

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The identification of selective inhibitors of the anti-apoptotic Bcl-2 family remains a principal target for cancer drug development. With the recent recognition of Mcl-1 as the primary Bcl-2 family member expressed in solid tumors and its ability to enable therapeutic resistance, identification of peptides that specifically bind to Mcl-1 has become critical for the development of improved therapeutics. To identify novel peptides that bind to the BH3 cleft of Mcl-1, we screened a randomized twelve residue phage display library using a pan-active Bcl-2 small-molecule inhibitor. This screen identified a unique non-canonical BH3 sequence, rBH3, which selectively binds to Mcl-1 over Bcl-xL. NMR analysis of the rBH3 interaction with Mcl-1 shows that it binds to the BH3 binding groove and an alanine scan of the sequence highlights the key residues responsible for its binding. A search for proteins with the rBH3 motif has identified a number of interesting targets which have previously been associated with apoptosis regulation. Thus we believe that this sequence represents a unique, Mcl-1-specific peptide sequence that may identify a previously unknown family of Mcl-1 interacting proteins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 8. doi:10.1158/1538-7445.AM2011-8