Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds

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Abstract
Oncogenic RAS proteins are important for driving tumour formation, and for maintenance of the transformed phenotype, and thus their relevance as a cancer therapeutic target is undeniable. We focused here on obtaining peptidomimetics, which have good pharmacological properties, to block Ras–effector interaction. Computational analysis was used to identify hot spots of RAS relevant for these interactions and to screen a library of peptidomimetics. Nine compounds were synthesized and assayed for their activity as RAS inhibitors in cultured cells. Most of them induced a reduction in ERK and AKT activation by EGF, a marker of RAS activity. The most potent inhibitor disrupted Raf and PI3K interaction with oncogenic KRAS, corroborating its mechanism of action as an inhibitor of protein–protein interactions, and thus validating our computational methodology. Most interestingly, improvement of one of the compounds allowed us to obtain a peptidomimetic that decreased the survival of pancreatic cancer cell lines harbouring oncogenic KRAS.
Funding Information
  • Ministerio de Educación, Cultura y Deporte (FPU, predoctoral fellowship)
  • Departament de Salut, Generalitat de Catalunya (PFI predoctoral Fellowship)
  • Universitat de Barcelona (Predoctoral Fellowship)
  • Ministerio de Ciencia e Innovación (PID2019-105483RB-I00/AEI/10.13039/501100011033.)
  • Ministerio de Economía y Competitividad (SAF2016-76239-R)

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