Novel Peptidic Agents for Targeting Chemoresistant Anti-Apoptotic Mcl-1

Technology

Mcl-1, along with other members of the Bcl-2 family, blocks apoptosis by binding to short helices in pro-apoptotic proteins, inhibiting their homo-oligomerization and activation. Synthetic peptides that bind Mcl-1 can be used to prevent this interaction by physically blocking the binding site on Mcl-1 and preventing its inhibition of pro-apoptotic proteins. This has been demonstrated using the short peptide MS1, which binds Mcl-1 and selectively induces mitochondrial permeabilization (MOMP) in Mcl-1-dependent cancer cells.  This process has been improved upon with the use of hydrocarbon stapling to stabilize the peptide and promote its cellular uptake. Concurrently, a peptide library screen revealed two sequence modifications of MS1— each a substitution of an amino acid residue— that enhance binding to Mcl-1 without compromising a high degree of specificity or requiring hydrocarbon stapling for their activity. However, these high-affinity peptides still require a means for cell entry (e.g., nanoparticle delivery). In combination with a delivery system, the optimized peptides have therapeutic potential as highly selective Mcl-1 inhibitors. 

Problem Addressed

Mcl-1 is an oncogene that is overexpressed in many cancers and confers resistance to chemotherapeutic agents. Mcl-1 belongs to a family of anti-apoptotic proteins with homology to B-cell lymphoma 2 (Bcl-2). Inhibition of Mcl-1 and related proteins using potent, selectively binding small molecules is a promising avenue for therapy; however, no such small molecule has been identified for Mcl-1. Synthetic peptides designed to selectively inhibit Mcl-1 are an alternative to small molecules. Upon delivery into the cell, the peptides bind and inhibit Mcl-1, making them candidates for development as cancer therapeutics. 

Advantages

• High binding affinity  
• Mcl-1 specific binding

Related Technologies

This case is related to MIT technology: #17695

Publications

Rezaei Araghi, R., Ryan, J. A., Letai, A., & Keating, A. E. (2016). Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains. ACS Chemical Biology, 11(5), 1238-1244. doi: 10.1021/acschembio.5b01002.