2. Academic Validation
  3. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment

Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment

  • Nat Commun. 2018 Aug 9;9(1):3169. doi: 10.1038/s41467-018-05707-2.
Camilo E Quevedo 1,  Abimael Cruz-Migoni 1 2,  Nicolas Bery 1,  Ami Miller 1,  Tomoyuki Tanaka 3 4,  Donna Petch 3,  Carole J R Bataille 5,  Lydia Y W Lee 6,  Phillip S Fallon 6,  Hanna Tulmin 1 7,  Matthias T Ehebauer 1 8,  Narcis Fernandez-Fuentes 2 9,  Angela J Russell 5,  Stephen B Carr 2 10,  Simon E V Phillips 2 10,  Terence H Rabbitts 11
Affiliations

Affiliations

  • 1 Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
  • 2 Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxon, OX11 0FA, UK.
  • 3 Leeds Institute for Molecular Medicine, St James University Hospital, Leeds, LS9 7TF, UK.
  • 4 Research & Development, Sanofi K.K., Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo, 163-1488, Japan.
  • 5 Chemistry Research Laboratory, 12 Mansfield Rd, Oxford, OX1 3TA, UK.
  • 6 Domainex, Chesterford Research Park, Little Chesterford, Saffron Walden, CB10 1XL, UK.
  • 7 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK.
  • 8 Oxford Drug Discovery Institute, Nuffield Department of Medicine Research Building, University of Oxford, Old Road Campus, Oxford, OX3 7FZ, UK.
  • 9 Institute of Biological, Environmental and Rural Sciences, University of Aberystwyth, Aberystwyth, SY23 3EB, UK.
  • 10 Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
  • 11 Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK. [email protected].
PMID: 30093669 DOI: 10.1038/s41467-018-05707-2
Abstract

Targeting specific protein-protein interactions (PPIs) is an attractive concept for drug development, but hard to implement since intracellular Antibodies do not penetrate cells and most small-molecule drugs are considered unsuitable for PPI inhibition. A potential solution to these problems is to select intracellular antibody fragments to block PPIs, use these antibody fragments for target validation in disease models and finally derive small molecules overlapping the antibody-binding site. Here, we explore this strategy using an anti-mutant Ras antibody fragment as a competitor in a small-molecule library screen for identifying RAS-binding compounds. The initial hits are optimized by structure-based design, resulting in potent RAS-binding compounds that interact with Ras inside the cells, prevent RAS-effector interactions and inhibit endogenous RAS-dependent signalling. Our results may aid RAS-dependent Cancer drug development and demonstrate a general concept for developing small compounds to replace intracellular antibody fragments, enabling rational drug development to target validated PPIs.

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