2. Academic Validation
  3. DNA-Encoded Macrocyclic Peptide Libraries Enable the Discovery of a Neutral MDM2-p53 Inhibitor

DNA-Encoded Macrocyclic Peptide Libraries Enable the Discovery of a Neutral MDM2-p53 Inhibitor

  • ACS Med Chem Lett. 2023 May 5;14(6):820-826. doi: 10.1021/acsmedchemlett.3c00117.
Anthony P Silvestri 1,  Qi Zhang 2,  Yan Ping 2,  Erik W Muir 1,  Jingsi Zhao 2,  Sai Kumar Chakka 1,  Gaonan Wang 2,  Walter M Bray 1,  Wenhua Chen 2,  Jennifer L Fribourgh 1,  Sarvind Tripathi 3,  Yunyun He 2,  Seth M Rubin 3,  Alexander L Satz 4,  Cameron R Pye 1,  Letian Kuai 5,  Wenji Su 2,  Joshua A Schwochert 1
Affiliations

Affiliations

  • 1 Unnatural Products, Inc., 2161 Delaware Ave. Suite A, Santa Cruz, California 95060, United States.
  • 2 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, United States.
  • 4 WuXi AppTec, Am Klopferspitz 19a, 82152 Martinsried, Germany.
  • 5 WuXi AppTec, 55 Cambridge Parkway, 8th Floor, Cambridge, Massachusetts 02142, United States.
PMID: 37312849 DOI: 10.1021/acsmedchemlett.3c00117
Abstract

Synthetic macrocyclic Peptides are an emerging molecular class for both targeting intracellular protein-protein interactions (PPIs) and providing an oral modality for drug targets typically addressed by biologics. Display technologies, such as mRNA and phage display, often yield Peptides that are too large and too polar to achieve passive permeability or oral bioavailability without substantial off-platform medicinal chemistry. Herein, we use DNA-encoded cyclic peptide libraries to discover a neutral nonapeptide, UNP-6457, that inhibits MDM2-p53 interaction with an IC50 of 8.9 nM. X-ray structural analysis of the MDM2-UNP-6457 complex revealed mutual binding interactions and identified key ligand modification points which may be tuned to enhance its pharmacokinetic profile. These studies showcase how tailored DEL libraries can directly yield macrocyclic Peptides benefiting from low MW, TPSA, and HBD/HBA counts that are capable of potently inhibiting therapeutically relevant protein-protein interactions.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149988
    MDM-2/p53 Interaction Inhibitor