Tales of macrocycle medchem: Balancing cell permeability and target binding — ASN Events

Tales of macrocycle medchem: Balancing cell permeability and target binding (#104)

Joshua Schwochert 1 , Anthony Silvestri 1 , Changfeng Cheng 1 , Jennifer Fribourgh 1 , Walter Bray 1 , Seth Rubin 2 , Cameron Pye 1
  1. UNNATURAL PRODUCTS INC., SANTA CRUZ, CA, United States
  2. Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA

Nearly all cyclic peptides found from ribosomally synthesized library techniques; e.g. phage display and mRNA display, are too large and far too polar for cell permeability.  To overcome this, we have utilized a non-traditional medicinal chemistry approach focused on large leaps in scaffold and pharmacophore space.  A model medicinal chemistry campaign will be discussed utilizing our chemistry and computational platform.  Through the use of iterative focused libraries and direct-to-biology screening we rapidly optimized a series of MDM2 binding cyclic peptides from unobservable intrinsic permeability to small-molecule-like permeability while improving potency 100-fold, yielding compounds with nM cell activity.  Efforts to improve the drug-likeness of de novo peptide ligands through macrocycle DNA-encoded libraries, will also be discussed.

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