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

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

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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