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

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.