Novel Peptides for the Treatment of Chemotherapy-resistant Cancers

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Novel peptides for the treatment of chemotherapy-resistant cancers
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Inventors
Professor Amy Keating
Department of Biology, MIT
External Link (web.mit.edu)
Raheleh Rezaei
Department of Biology, MIT
Managed By
Jon Gilbert
MIT Technology Licensing Officer
Patent Protection

Selective Mcl-1 Binding Peptides

PCT Patent Application Filed

Applications

Mcl-1-binding peptides may be useful in treating a variety of chemotherapy-resistant cancers such as adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). 

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. 

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, described here, 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. 

Advantages

  • High binding affinity  
  • Mcl-1 specific binding