Natural (and Unnatural) Small Molecules as Pharmacological Chaperones and Inhibitors in Cancer

  • Isabel Betancor-Fernández
  • David J. Timson
  • Eduardo Salido
  • Angel L. PeyEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 245)


Mutations causing single amino acid exchanges can dramatically affect protein stability and function, leading to disease. In this chapter, we will focus on several representative cases in which such mutations affect protein stability and function leading to cancer. Mutations in BRAF and p53 have been extensively characterized as paradigms of loss-of-function/gain-of-function mechanisms found in a remarkably large fraction of tumours. Loss of RB1 is strongly associated with cancer progression, although the molecular mechanisms by which missense mutations affect protein function and stability are not well known. Polymorphisms in NQO1 represent a remarkable example of the relationships between intracellular destabilization and inactivation due to dynamic alterations in protein ensembles leading to loss of function. We will review the function of these proteins and their dysfunction in cancer and then describe in some detail the effects of the most relevant cancer-associated single amino exchanges using a translational perspective, from the viewpoints of molecular genetics and pathology, protein biochemistry and biophysics, structural, and cell biology. This will allow us to introduce several representative examples of natural and synthetic small molecules applied and developed to overcome functional, stability, and regulatory alterations due to cancer-associated amino acid exchanges, which hold the promise for using them as potential pharmacological cancer therapies.


Gain of function Inhibitors Loss of function Natural effectors Pharmacological chaperones Protein function Protein stability Single amino acid exchange 



The authors acknowledge funding from the Spanish Ministry of Economy and Competitiveness, MINECO (BIO2015-66426-R and SAF2015-69796), from Junta de Andalucia (P11-CTS-07187) and FEDER funds.


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Isabel Betancor-Fernández
    • 1
  • David J. Timson
    • 2
  • Eduardo Salido
    • 1
  • Angel L. Pey
    • 3
  1. 1.Centre for Biomedical Research on Rare Diseases (CIBERER)Hospital Universitario de CanariasTenerifeSpain
  2. 2.School of Pharmacy and Biomolecular SciencesUniversity of BrightonBrightonUK
  3. 3.Department of Physical ChemistryUniversity of GranadaGranadaSpain

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