Targeting a Novel KRAS Binding Site: Application of One-Component Stapling of Small (5-6-mer) Peptides

  • J Med Chem. 2021 Dec 9;64(23):17287-17303. doi: 10.1021/acs.jmedchem.1c01334.
Gabriele Fumagalli  1  2 ,  Rodrigo J Carbajo  2 ,  J Willem M Nissink  2 ,  Jonathan Tart  3 ,  Rongxuan Dou  1 ,  Andrew P Thomas  2 ,  David R Spring  1
Affiliations
  • 1. Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW, U.K.
  • 2. Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 3. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
PMID: 34787423 DOI: 10.1021/acs.jmedchem.1c01334
Abstract

Ras proteins are central in the proliferation of many types of Cancer, but a general approach toward the identification of pan-mutant Ras inhibitors has remained unresolved. In this work, we describe the application of a binding pharmacophore identified from analysis of known Ras binding peptides to the design of novel peptides. Using a chemically divergent approach, we generated a library of small stapled peptides from which we identified compounds with weak binding activity. Exploration of structure-activity relationships (SARs) and optimization of these early compounds led to low-micromolar Binders of KRAS that block nucleotide exchange.

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